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Media Backgrounder - DRONEDARONE A NEW OPTION IN THE TREATMENT OF

By Clarence Morales,2014-11-26 16:57
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Media Backgrounder - DRONEDARONE A NEW OPTION IN THE TREATMENT OF

For non-US journalists only

    ?DRONEDARONE (MULTAQ)

    MEDIA BACKGROUNDER

    ?Dronedarone (brand name Multaq) is a new multi-channel blocking anti-arrhythmic compound

    developed by sanofi-aventis for the prevention and treatment of AF. In pivotal studies, dronedarone has shown efficacy in maintaining normal sinus rhythm (heart rhythm control) and additional control of ventricular rate (heart rate control) in patients with atrial fibrillation/atrial flutter (AF/AFL).

    1 Dronedarone blocks calcium, potassium and sodium channels, has antiadrenergic effectsand

    does not contain an iodine radical. Dronedarone did not cause thyroid or pulmonary toxicity in

    1clinical trials.

The dronedarone phase III clinical development

    1 The EURIDIS/ADONIS Studies

    The EURIDIS (EURopean trial In atrial fibrillation patients receiving Dronedarone for the

    maIntenance of Sinus rhythm) and ADONIS (American-Australian trial with DronedarONe In atrial

    fibrillation patients for the maintenance of Sinus rhythm) studies were pivotal phase III, double-

    blind, placebo-controlled trials with a common protocol. The studies were designed to assess the efficacy of dronedarone for the maintenance of normal sinus rhythm in patients with paroxysmal or persistent atrial fibrillation who had been cardioverted. The EURIDIS trial was conducted in Europe while the ADONIS trial took place in the US, Canada, Argentina, Australia and South Africa.

    Patients enrolled in both trials (n=1,237) were in Normal sinus rhythm (NSR) at least one hour at the time of randomisation and had at least one ECG-documented atrial fibrillation in the previous three months. In both trials, 1718 percent of patients had mild HF (NYHA class 1 or 2) and 22

    percent had coronary artery disease.

    Page 1 of 8

    Patients were randomised in a 2:1 ratio to receive either dronedarone 400 mg BID or placebo and were treated for 12 months. The primary endpoint of each study was the time from randomisation to the first documented AF recurrence, defined as an episode lasting for 10 minutes or more.

EURIDIS/ADONIS

    Studydesign

    Primaryefficacycriterionfromrandomisation to 1 year

    ADONIS : (n=208)Screeningperiod

    EURIDIS : (n=201)Placebo

    ADONIS : (n=417)D-6 to D1

    EURIDIS : (n=411)Dronedarone 400 mg bid

    Sinus rhythmfor atleast1 hour

    atthetimeofrandomisation

    andwithatleastoneECG-

    documented AF episode

    in thelast3 months.

EURIDIS/ADONIS Key Findings

    In the EURIDIS and ADONIS trials, the median times to arrhythmia recurrence were significantly longer for dronedarone than placebo for the primary endpoint. For the EURIDIS trial, 96 days versus 41 days (p=0,014) and for the ADONIS trial, 158 days versus 59 days (p=0,002).

    In the two trials, at 12 months, significantly fewer patients experienced an AF/AFL recurrence in the dronedarone group compared to the placebo groups. For the EURIDIS trial, 67.1 percent versus 77.5 percent (p=0,014) and for the ADONIS trial, 61.1 percent versus 72.8 percent (p=0,002).

    Page 2 of 8

    In both studies, dronedarone also significantly reduced the ventricular rate during arrhythmia recurrence, a secondary endpoint. This therapeutic effect is also referred to as rate control strategy, which consists of reducing the heart rate.

    A post-hoc analysis also showed that in the combined studies, dronedarone significantly reduced the rate of the combined end point of hospitalisation or death compared to placebo. This important finding is being prospectively explored in an ongoing morbidity and mortality trial.

EURIDIS/ADONIS Tolerability and Safety Overview

    In the dronedarone arm of the studies, no episodes of ‘’torsades de pointes,’’ a serious ventricular

    arrhythmia observed with some existing treatments, were reported at one year and the incidence of adverse events (pulmonary toxicity, thyroid and liver dysfunction) was not significantly increased. In both studies, hyperthyroidism occurred less frequently in the dronedarone group versus placebo (8.4 percent vs. 14.1 percent, P=0.0024) and elevated serum creatinine concentrations, which in some cases were reversible, occurred more frequently in the dronedarone group versus placebo (2.4 percent vs. 0.2 percent, P=0.0039) without impact on renal function. The most common adverse events occurring in more than two percent of dronedarone treated patients (not statistically different from placebo), included cough, dyspnoea, hypothyroidism, bradycardia/conduction block, heart failure/shock, diarrhea, nausea, and liver function abnormalities.

    2The ERATO Study

    The ERATO (Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial

    fibrillation) study was a multinational, multicentre, double-blind, randomised study to assess the efficacy and tolerability of dronedarone in the control of ventricular rate in patients with permanent AF at rest. It also assessed the efficacy of dronedarone in reducing ventricular rate during exercise without decreasing exercise tolerance.

    Page 3 of 8

    ERATO: Study designERATO Study Design

    Randomisation

    M6 + 10-15 Dronedarone: Placebo = 1:1HolterHolterdays

    End of Dronedarone400 mg bidTreatment

    D-15 to PlaceboAF > 6 monthsD1

    Screeningperiod

    D144 months6 months

    Trial Population Placebo nDronedarone nTotal n

    ERATO8985174

    The study included patients (n=174) who had documented, symptomatic, permanent AF of >six months’ duration for which cardioversion was not considered and a resting ventricular rate ?80 bpm. They were randomised to either dronedarone 400 mg BID (n=85) or placebo (n=89) and followed for six months.

ERATO Key Findings

    In the dronedarone group, there was a significant decrease in both mean rate (86.5 bpm reduced to 76.2 bpm for dronedarone) and maximum rate with exercise (152.6 bpm reduced to 129.7 bpm), without impairing exercise capacity. There was no change in either metric in the placebo group. This change was observable after 14 days and lasted throughout the duration of the study (-8.8 bpm at 4 months; p<0.001).

    The addition of dronedarone to standard background therapy (calcium antagonists, beta blockers or digoxin) produced a statistically significant additional decrease in ventricular response rate to AF.

ERATO Tolerability and Safety Overview

    The overall incidence of treatment-emergent adverse events was slightly higher in the dronedarone arm than in the placebo group. However, the incidence of serious treatment-emergent adverse events, premature discontinuations for adverse events and deaths was similar in the two groups. The level of gastrointestinal disturbances, the most frequent serious adverse event, was not statistically different between the two groups (20 percent for dronedarone vs. 14

    Page 4 of 8

    percent for placebo). No cases of pro-arrhythmia or torsades de pointes were reported in either treatment group. There was also no evidence of thyroid or pulmonary toxicity in either treatment group.

    3The ANDROMEDA Study

ANDROMEDA stands for: “ANtiarrhythmic trial with DROnedarone in Moderate to

    severe CHF Evaluating morbidity DecreAse”. The ANDROMEDA study was a morbid

    mortality study conducted in patients with left ventricular dysfunction and a recent hospitalization for a severe unstable congestive heart failure, within the month preceding inclusion into the study. These patients were not selected based on AF/AFL history. ANDROMEDA was representative of a severe unstable heart failure population. The primary objective of this trial was to evaluate the potential benefit of the new anti-arrhythmic dronedarone on hospitalization for worsening heart failure or death in thesepatients. Due to an unbalance in the number of deaths in the dronedarone group as compared to placebo (25 vs 12), the study was stopped in 2003, 6 months after study start (627 patients were included at that time) following a recommendation of the Data Safety Monitoring Board.

    Patients did not necessarily have to present with concomitant atrial fibrillation to be included in the study (less than 30% to 40% of patients had concomitant AF at randomization). These patients were not selected based on AF/AFL history.

    The excess of deaths in ANDROMEDA were cardiac non-sudden deaths and were related to worsening heart failure. There were no documented cases of Torsades de pointes, suggesting that Multaq was not pro-arrhythmic.

    It has been observed in a post-hoc analysis, that there was an excess of discontinuation of ACE-Inhibitors (ACE) or Angiotensin Receptor Blockers (ARB), , known to save lives and reduce morbidity in CHF patients, in the dronedarone group. :

    A usually mild increase (10-15%) in serum creatinine is observed at initiation of Multaq, due to competitive inhibition of tubular creatinine secretion not indicative of renal toxicity. It was hypothesised that the more frequent ACE-I or ARB discontinuation was related to the creatinine increase known to occur with dronedarone and that was interpreted by investigators as a signal of ACE/ARBs renal toxicity, and motivated their discontinuation.

    There was no evidence of any pro-arrhythmic potential or torsade de pointes in this high risk population of CHF patients.

    Page 5 of 8

The ATHENA Study

    Given the good safety and efficacy results in EURIDIS/ADONIS and ERATO, it was decided to conduct an outcome morbidity and mortality study (ATHENA) in the targeted AF population, with patients with high cardiovascular risk in order to provide a deeper assessment of both efficacy and safety of dronedarone including the absence of negative impact on mortality. ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of

    Dronedarone 400 mg Bid for the Prevention of Cardiovascular Hospitalization or Death from Any

    Cause in PatiENts with Atrial Fibrillation/Atrial Flutter) was a double-blind, placebo-controlled

    morbidity and mortality study and is the first study where an antiarrhythmic is evaluated in terms of efficacy and safety in a large risk AF population with hard endpoints.

    ATHENA has objectives to show a potential benefit of dronedarone on a hard primary composite endpoint of all-cause mortality combined with cardiovascular hospitalisation and prospectively confirm the positive trend observed in EURIDIS-ADONIS.

     ATHENA study design

     Dronedarone 400 mg twice a day n=2301 Patients with atrial fibrillation or atrial

    Double fibrillation as well

    blind R as additional risk factors Placebo n=2327

    12 to 30

    months

    The pre-specified secondary endpoints were death from any cause, cardiovascular death and hospitalisation for cardiovascular reasons. The secondary pre-specified main safety endpoint was the incidence of treatment emergent adverse events (time of observation for treatment emergent adverse events) which were classified as follows: serious adverse events, adverse events leading to study drug discontinuation, all adverse events.

    Page 6 of 8

    Patients (n~4,600) had paroxysomal or persistent AF, and were >75 years of age or were 70-75 years with a high-risk marker (hypertension, diabetes, previous cerebrovascular event, left atrium size >50 mm or left ventricular ejection fraction <40 percent). They were randomised to receive dronedarone 400 mg BID or placebo and with a median follow-up of for 540 days.

In ATHENA, the use of a background of standard care for the patient’s cardiac condition

    according to published guidelines was recommended and in the overall study population most patients were treated by multiple evidence based cardiovascular and rate control medications not only before but after enrolment (oral anticoagulant, Beta Blockers, ACE inhibitors/ARB’s,

    Statins…).

    ATHENA patients were recruited at 551 centres in 37 countries: Argentina, Australia, Austria, Belgium, Canada, Chile, China, Czech Republic, Finland, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Malaysia, Mexico, Morocco, New Zealand, Norway, Philippines, Poland, Portugal, Russia, South Africa, Singapore, South Korea, Spain, Sweden, Taiwan, Thailand, The Netherlands, Tunisia, Turkey, UK and the U.S.

    Results of the ATHENA trial have been released in San Francisco, at Heart Rhythm 2008, the

    thHeart Rhythm Society's 29th Annual Scientific Sessions on May 15, 2008.

The DYONISOS Study

    Dyonisos study is an ongoing randomized double blind trial to evaluate efficacy and safety of dronedarone (400mg BID) versus amiodarone (600mg daily for 28 days, then 200mg daily thereafter) for at least 6 Months for the maintenance of sinus rhythm in patients with atrial fibrillation. The estimated enrolment is 472 patients and the study started in June 2007. The objective of this study is to compare the efficacy and safety of dronedarone to that of amiodarone for the treatment of patients with AF.

    The primary efficacy endpoint is treatment failure defined as recurrence of atrial fibrillation or premature study drug discontinuation for intolerance or lack of efficacy. The main safety endpoint is occurrence of Thyroid, Hepatic, Pulmonary, Neurological, Skin, Eye or Gastrointestinal specific events or premature study drug discontinuation following any adverse event. Patients enrolled in the study have documented atrial fibrillation for more than 72 hours for whom cardioversion and

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antiarrhythmic treatment is indicated in the opinion of the investigator and under oral

    anticoagulation.

     DIONYSOS study design

AMIODARONE

     n472 60mg daily 200mg daily

    Patients with documented AF of 72 hours 28 days 6 months + Indicated for cardioversion R antiarrythmic treatment

    Under oral anticoagulation DRONEDARONE

    40mg BID

References

    1. S. Hohnloser. ERIDIS and ADONIS: Maintenance of sinus rhythm with dronedarone in patients with atrial fibrillation or flutter. Abstract presented at the European Society of Cardiology Congress 2004; August 28-September 1, 2004; Munich, Germany. 2. Davy JM. ERATO: The efficacy and safety of dronedarone as a novel rate control agent for the treatment of atrial fibrillation Abstract: P3042 Abstract presented at the European Society of Cardiology Congress 2005; September 3-7, 2005; Stockholm, Sweden.

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