More on AF

1. Overview
2. Determine the most appropriate dose of dronedarone to prevent of Atrial Fibrillation: The DAFNE study
3. Maintenance of Sinus Rhythm: The EURIDIS /ADONIS Studies
4. Effect of dronedarone on Rate Control: The ERATO Study
5. Addressing Morbidity and Mortality in AF: The ATHENA Study
6. Further Characterisation of Dronedarone

1. Overview

Dronedarone (Multaq®) is an investigational treatment and the only Anti-Arrhythmic Drug (AAD) to have shown a significant reduction in morbidity and mortality in atrial fibrillation/atrial flutter (AF/AFL) patients. Dronedarone, discovered and developed by sanofi-aventis, has been studied in a clinical development programme including more than 6,700 patients. It is one of the major therapeutic innovations in AF for the last twenty years and has been granted a priority review by the U.S. Food and Drug Administration (FDA). A registration dossier is also under regulatory review by the European Medicines Agency (EMEA).

Dronedarone’s comprehensive clinical development programme provides compelling evidence that a twice-daily dose of 400mg reduces symptomatic/asymptomatic episodes of AF; decreases rapid ventricular rate; and significantly reduces cardiovascular hospitalisations or death in patients with AF.^2,3,4

Key results from the ATHENA study, first presented at the Heart Rhythm Society Congress in May, 2008 and now published in the New England Journal of Medicine showed that dronedarone, decreased the risk of cardiovascular hospitalisation or death from any cause in patients with AF by a statistically significant 24 percent (p<0.001) compared with placebo and reduced the risk of cardiovascular hospitalisation by 26 percent (p<0.001)⁴.

Dronedarone has a favourable safety profile as evidenced by a low risk of pro-arrhythmiaⁱ (including torsades de pointesⁱ, a serious ventricular arrhythmia) and extracardiac organ toxicity (such as thyroid or pulmonary toxicity).^2,4

Dronedarone is easy to use for patients and physicians with a convenient fixed dose regimen (400mg) and no loading dose. Dronedarone can be administered in an outpatient setting and requires minimal monitoring.

2. Determine the most appropriate dose of dronedarone to prevent of Atrial Fibrillation: The DAFNE study

2.1 Study Design

The DAFNE (Dronedarone Atrial FibrillatioN Study After Electrical Cardioversionⁱ) study¹ was a phase II, double blind randomized, trial that aimed to determine the most appropriate dose of dronedarone for preventing recurrence of AF after cardioversion in patients with persistent AF.

Patients enrolled (n=199) had persistent AF scheduled for elective cardioversion.

Patients were randomised to receive one of three doses of dronedarone: 400, 600, 800 mg BID or placebo. The primary endpointⁱ was time to first documented AF recurrence.

 

Dafne Study
The DAFNE study was published in the European Heart Journal (EHJ) on June, 2003.

2.2 Key Findings

DAFNE trial showed that dronedarone 400 mg bid significantly prolonged time to first AF recurrence. Within 6 months of follow-up, the time to AF recurrence increased on dronedarone 400 mg bid, with a median time of 60 days vs. 5.3 days in the placebo group with a relative risk reduction of 55 percent (p=0,001). With higher doses (600 and 800 mg BID) no significant change was seen indicating a lack of dose effect.

2.3 Safety and Tolerability Overview

The safety and tolerability of dronedarone was good with no incidence of proarrhythmic events including torsades de pointes. Drug-induced QT prolongation was noted only in the 1600 mg group. No evidence of organ (thyroid, ocular or pulmonary) toxicity was found.

3. Maintenance of Sinus Rhythm: The EURIDIS /ADONIS Studies

3.1 Study Design

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) studies² 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 AF who had been cardioverted. The EURIDIS trial was conducted in Europe while the ADONIS trial took place in the U.S., Canada, Argentina, Australia and South Africa.

Patients enrolled in both trials (n=1,237) had been in normal sinus rhythm (NSR) for at least one hour at the time of randomisation and had at least one ECG-documented AF episode in the previous three months. In both trials, 17–18 percent of patients had mild heart failure (and 22 percent had coronary artery disease).

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.

The EURIDIS/ADONIS study was published in the New England Journal of Medicine (NEJM) on 5th September, 2007.

 

Euridis Adonis

3.2 Key Findings

EURIDIS and ADONIS trials showed that dronedarone reduces the recurrence of symptomatic and asymptomatic episodes of AF.

In these two studies, the median times to arrhythmia recurrence were significantly longer for dronedarone than placebo for the primary endpoint: 96 days vs. 41 days (p=0.01) in the EURIDIS trial and 158 days vs. 59 days (p=0.002) in the ADONIS trial.

In both trials, at 12 months, significantly fewer patients experienced an AF/AFL recurrence in the dronedarone groups compared with the placebo groups: in the EURIDIS trial, 67.1 percent vs. 77.5 percent (p=0.01) and in the ADONIS trial, 61.1 percent vs. 72.8 percent (p=0.002). In both studies, dronedarone also significantly reduced the ventricular rate during arrhythmia recurrence, a secondary endpoint.

For the two trials combined, at 12 months, dronedarone was significantly more effective than placebo at decreasing the occurrence of symptomatic episodes of AF, 62.3 percent of patients on dronedarone were free of symptomatic AF recurrence at 1 year vs. 74,7 percent on placebo (p<0.001).

A post-hoc analysis of the combined studies also showed that dronedarone significantly reduced of 27 percent, the rate of the combined end point of hospitalisation or death compared with placebo: 22.8 percent of patients in the dronedarone group had been hospitalised or had died at 12 months vs. 30.9 percent in the placebo arm (p=0.01). This important finding was prospectively explored in the landmark ATHENA trial⁴.

3.3 Safety and Tolerability Overview

In the dronedarone arm of the studies, no episodes of torsades de pointes, 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 vs. placebo (8.4 percent vs. 14.1 percent, P=0.002). Elevated serum creatinine concentrations, which in some cases were reversible, occurred more frequently in the dronedarone group vs. placebo (2.4 percent vs. 0.2 percent, P=0.004) 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, diarrhoea nausea, and liver function abnormalities.

4. Effect of dronedarone on Rate Control: The ERATO Study

4.1 Study Design

ERATO (The Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation), a randomised, double blind, placebo-controlled, parallel group study, was conducted in 174 adult patients with symptomatic, permanent AF of at least six months’ duration, recruited from 38 centres in nine European countries.

ERATO was the first dronedarone study⁵ in patients with permanent AF. The pivotal EURIDIS-ADONIS trials in the maintenance of sinus rhythm demonstrated that dronedarone significantly decreased ventricular rate during a first recurrence of AF in paroxysmal and persistent AF patients.

The study included patients who had documented, symptomatic, permanent AF 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

 

4.2 Key Findings

The ERATO study demonstrated, in patients with permanent AF, that dronedarone on top of other rate control agents, significantly reduces mean 24 hour ventricular rate. The mean heart rateⁱ reduction was 11.7 beats per minute (p< 0.0001) with dronedarone compared with placebo, which is clinically relevant and highly statistically significant. The rate-controlling effect of dronedarone was sustained throughout the six-month trial and was additive to the effect of other rate control therapies. Dronedarone also significantly reduced maximal ventricular frequency during exercise by 24.5 beats per minute (p<0.0001) without impairing patients exercise capacity.

4.3 Safety and Tolerability Overview

In ERATO, the incidence of adverse events in the dronedarone arm was not statistically different although slightly higher compared with the placebo group. Gastrointestinal disturbances and mild increases in mean serum creatinine levels were observed more frequently in the dronedarone group, in accordance with previous studies. Creatinine increase occurred early after treatment initiation and reached a plateau after seven days. Creatinine levels returned to baseline within one week after treatment discontinuation with no impact on renal function. No evidence of thyroid or pulmonary fibrosis was observed with dronedarone and no torsades de pointes was reported during the six-month follow-up.

5. Addressing Morbidity and Mortality in AF: The ATHENA Study

5.1 Study Design

The landmark ATHENA study⁴ is the largest antiarrhythmic drug clinical trial ever conducted in AF patients and the first with morbidity-mortality as an endpoint. ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalisation or Death from Any Cause in PatiENts with Atrial Fibrillation/Atrial Flutter) is a double blind placebo-controlled randomised study in patients with AF, conducted in more than 550 sites in 37 countries and enrolled a total of 4,628 patients.

The ATHENA results were first presented at the late breaking clinical trial session of Heart Rhythm 2008, the Heart Rhythm Society's 29th Annual Scientific Sessions in San Francisco, USA and were published in the New England Journal of Medicine on 12th February 2009.

 

 
Athena


The ATHENA study objectives were designed to show a potential benefit of dronedarone on the primary composite endpoint of all-cause mortality combined with cardiovascular hospitalisation compared with placebo. The pre-specified secondary endpoints were death from any cause, cardiovascular death and hospitalisation for cardiovascular reasons. The pre-specified safety endpoint was the incidence of treatment emergent adverse events (between first study drug intake and last study drug intake plus 10 days) including all adverse events, serious adverse events and adverse events leading to study drug discontinuation.

The patients studied in ATHENA were either 75 years of age or older (with or without cardiovascular risk factors) or below 75 years of age with at least one additional cardiovascular risk factor (hypertension, diabetes, previous ischemic cerebrovascular event, left atrium size greater than 50 mm or left ventricular ejection fraction lower than 40 percent). Patients with recently decompensated heart failure or in New York Heart Association (NYHA) class IV were excluded. Patients were randomised to receive dronedarone 400 mg BID or placebo, with a mean follow-up of 21 months.

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 anticoagulants, beta blockers, calcium channel blockers, ACE inhibitors/ARBs, statinsⁱ).

ATHENA patients were recruited at 550 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.

5.2 Key Findings

The ATHENA study showed that dronedarone decreased the risk of cardiovascular hospitalisation or death by a statistically significant 24 percent (31.9 percent vs. 39.4 percent, p<0.001), meeting the study’s primary endpoint.

The authors’ findings, as reported in the New England Journal of Medicine, showed a significant decrease in the risk of cardiovascular death by 29 percent (p=0.03) in patients with AF. Dronedarone significantly decreased the risk of arrhythmic death by 45 percent (p=0.01) and there were numerically fewer deaths (16 percent) from any cause in the dronedarone group compared to placebo (p=0.18). First cardiovascular hospitalisation was reduced by 26 percent (p<0.001) in the dronedarone group.

5.3 Safety and Tolerability Overview

Reported significant adverse events (p < 0.001) in the dronedarone arm vs. placebo arm included diarrhea (9.7 percent vs. 6.2 percent), nausea (5.3 percent vs. 3.1 percent), bradycardia (3.5 percent vs. 1.2 percent), QT-interval prolongation (1.7 percent vs. 0.6 percent); skin disorders (10.3 percent vs. 7.6 percent) consisting mainly of rash, and an increase in blood creatinine (4.7 percent vs. 1.3 percent)*. There was no difference in permanent study drug discontinuation between dronedarone and placebo (30.2 percent vs. 30.8 percent).

* The mechanism of blood creatinine increase was well defined in a separate study of healthy volunteers and is not indicative of renal toxicity

5.4 ATHENA Strokeⁱ Post Hoc Analysis⁶

The ATHENA stroke post-hoc analysis was conducted in order to confirm the consistent benefit of dronedarone in reducing major cardiovascular complications in AF or AFL patients, such as stroke, which is a leading cause of cardiovascular hospitalisation or death in this patient population. Cardiovascular hospitalisations were a component of the primary endpoint. These post-hoc data were presented at the European Society of Cardiology (ESC) congress 2008, in Munich, Germany and showed that dronedarone decreased the risk of stroke (ischemic or haemorrhagic) compared with placebo by 34 percent (46 vs. 70 stroke events respectively; p=0.027) in AF/AFL patients adequately treated by standard therapy including antithrombotics.

For more information, please refer to the sanofi-aventis press release issued in September 2008: Further Analysis From ATHENA Study Showed that Multaq® (dronedarone) Reduced the Risk of Stroke in Patients With Atrial Fibrillation

5.5 ATHENA Hospitalisation Post Hoc Analysis⁷

AF is a leading cause of hospitalisation for arrhythmia⁷ representing one third of arrhythmia hospitalisations.8 AF hospitalisations have increased two to three-fold in the U.S. in recent years9 and 70 percent of the cost of AF management is driven by inpatient care and interventional procedures.10 Cardiovascular hospitalisation was a component of the primary endpoint of the ATHENA study. A further post hoc analysis was conducted in order to better understand the impact of dronedarone on hospitalisation burden within the AF/AFL population.

These post hoc data were presented at the American Heart Association (AHA) Scientific Sessions in November 2008 in New Orleans, USA,7 and showed that dronedarone significantly reduced the total number of hospital days by 28 percent (p<0.001) vs. placebo (9,995 days vs. 13,986 days), and decreased the total length of time spent in hospital for cardiovascular reasons by 35 percent (p<0.001; 5,875 days vs. 9,073 days).

In addition to demonstrating a 37 percent (p<0.001) reduction of AF-related hospitalisations, dronedarone reduced the incidence of first non-AF related CV hospitalisation (e.g. myocardial infarction or unstable angina) by 14 percent (p=0.016). Dronedarone did not increase the incidence of non-cardiovascular hospitalisations in comparison to the placebo arm.

For more information, please refer to the sanofi-aventis press release issued in November 2008: Dronedarone (Multaq®) Reduced the Incidence and Duration of Hospitalization in Patients with Atrial Fibrillation

5.6 ATHENA Rhythm and Rate Post Hoc Analysis¹¹

A second post hoc analysis from ATHENA, also presented during the AHA 2008 congress, confirmed the rhythm and rate controlling properties of dronedarone, which had previously been demonstrated in lower risk populations in the EURIDIS, ADONIS and ERATO trials. This analysis showed that dronedarone reduced the incidence of first AF recurrence by 25 percent in patients in sinus rhythm at study initiation (p<0.001), and the incidence of first electrical cardioversion by 31 percent (p<0.001), compared with placebo.

Dronedarone also decreased mean heart rate during AF to 78 beats per minute, compared with 87 for placebo (p<0.001). Fewer patients developed permanent AF during the study in the dronedarone group – 178 patients (7.7 percent) compared with 295 patients (12.7 percent) in the placebo arm (p<0.001). In these patients, the non-significant reduction of CV hospitalisation or death was 26 percent lower for those receiving dronedarone (p=0.096). These results are consistent with the overall study results.

Find more information in the sanofi-aventis press release issued in November 2008: Dronedarone (Multaq®) Reduced the Incidence and Duration of Hospitalization in Patients with Atrial Fibrillation

6. Further Characterisation of Dronedarone

6.1 Experience in Patients with Decompensated Heart Failure: The ANDROMEDA Study¹²

ANDROMEDA stands for: ANtiarrhythmic trial with DROnedarone in Moderate to severe CHF Evaluating morbidity DecreAse. The study was conducted to evaluate the benefit of dronedarone in heart failure patients with a recent severe episode of their heart condition (recent hospitalisation for decompensated systolic heart failure). These patients were not selected based on a history of AF or AFL.

Despite the fact that the primary endpoint (death or hospitalisation for worsening heart failure) did not differ between the two groups, the Independent Drug and Safety Monitoring Board recommended an early trial discontinuation due to an increase in the number of deaths in the dronedarone arm vs. the placebo arm (25 vs. 12 patients, p=0.03). These deaths were predominantly related to worsening heart failure in this patient population. There was no significant difference between placebo and dronedarone patients for arrhythmic events and sudden deaths. 627 patients have been included before the discontinuation of the trial.

Andromeda has helped characterise the population that could benefit from dronedarone. The ATHENA trial integrated the lessons of the overall clinical development programme including ANDROMEDA key learnings.

6.2 Efficacy and Safety Profile of Dronedarone vs. Amiodarone: The DIONYSOS Study13

The DIONYSOS study, is a short term study evaluating the efficacy and safety of dronedarone (400mg BID) vs. amiodarone (600mg daily for 28 days, then 200mg daily thereafter) in 504 patients with persistent AF eligible for electrical cardioversion. The primary endpoint of the trial was a combined primary endpoint of ECG-documented AF recurrence or premature study drug discontinuation for intolerance or lack of efficacy. A Main Safety Endpoint (MSE) was pre-specified and included predefined thyroid, hepatic, pulmonary, neurological, skin, ocular and gastrointestinal adverse events well as premature drug discontinuation due to adverse events. An analysis of the individual components of the MSE was pre-specified as well as an analysis excluding the gastrointestinal component to help a clinically meaningful interpretation of the overall results.

In the DIONYSOS study, dronedarone showed a decrease of safety events vs. amiodarone but more occurrences of the composite primary endpoint (AF recurrence or premature drug discontinuation for intolerance or lack of efficacy).

There were 184 patients (73.9 percent) who reached the primary endpoint in the dronedarone arm as compared to 141 (55.3 percent) in the amiodarone arm (p<0.001). In the primary endpoint, AF after electrical cardioversion occurred in 36.5 percent of patients in the dronedarone arm vs. 24.3 percent of patients in the amiodarone arm. Patients on amiodarone tended to experience more premature drug discontinuation (34 vs. 26) than patients on dronedarone.

DIONYSOS showed a decrease of 20 percent favouring dronedarone vs. amiodarone (83 vs. 107, p=0.1291) in the predefined main safety endpoint. The predefined main safety endpoint included thyroid, hepatic, pulmonary, neurological, skin, ocular, and gastrointestinal adverse events as well as premature study drug discontinuation due to any adverse event. In the dronedarone arm less thyroid events (2 vs. 15), neurological events (3 vs. 17) and premature study drug discontinuation due to any adverse events (13 vs. 28) was observed. In contrast, gastrointestinal events (diarrhea, vomiting, nausea) were more frequent in the dronedarone arm (32 vs. 13), consistent with previously reported studies.

When excluding GI side effects from the main safety endpoint, as also predefined in the protocol, there was a statistically significant decrease of 39 percent favouring dronedarone (61 vs. 99 / p=0.0021). Less bradycardia (8 vs. 22) and less pronounced QTc prolongation (27 vs. 52) was seen in the dronedarone arm than the amiodarone arm and no torsades de pointes were reported in the study.

While the DIONYSOS study was not designed to assess cardiovascular morbidity or mortality which was evaluated with long term treatment with dronedarone in the landmark ATHENA trial, there were less death reported in the dronedarone arm than in the amiodarone arm during the treatment period (2 vs. 5).

For more information’s please refer to the sanofi-aventis press release issued in December 2008: DIONYSOS Study Results Showed the Respective Profiles of Dronedarone and Amiodarone.


References :

1. Touboul P et al. Eur Heart J.  2003;24:1481-7
2. Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, Radzik D, Aliot EM, Hohnloser SH; EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007 Sep 6;357(10):987-99.
3. Davy JM. Herold M et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillationⁱ: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J. 2008 Sep;156(3):527.e1-9.
4. Hohnloser S. H., Crijns H. J. G. M., van Eickels M, et al. Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation, N Engl J Med 2009; 360:668-78.
5. Davy JM. Herold M et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J. 2008 Sep;156(3):527.e1-9.
6. Connolly SJ. ATHENA: The effect of dronedarone on cardiovascular outcomes and stroke in patients with atrial fibrillation. European Society of Cardiology Congress 2008; September 3, 2008; Munich, Germany. Clinical trials update
7. Torp-Pedersen C, Page RL, Connolly SJ, et al. The Effect of Dronaderone on Hospitalisations in Patients with Atrial Fibrillation. Results from the ATHENA Study. Scientific Sessions, American Heart Association, New Orleans, USA. November 2008
8. Fuster V et al. ACC/AHA/ESC Guidelines. European Heart Journal 2006; 27: 1979–2030.
9. Wattigney WA, Mensah GA & Croft JB. Increasing trends in hospitalisation for atrial fibrillation in the US 1985 through 1999 Implications for primary prevention. Circulation. 2003;108:711-716.
10. Ringborg A, Nieuwlaat R, Lindgren P, Jönsson B, Fidan D, Maggioni AP, Lopez-Sendon J, Stepinska J, Cokkinos DV, Crijns HJ. Costs of atrial fibrillation in five European countries: results from the Euro Heart Survey on atrial fibrillation. Europace. 2008 Apr;10(4):403-11. Epub 2008 Mar 7.
11. Page RL, Connolly SG, Crijns HJGM, et al.  Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation: Insights from the ATHENA trial Scientific Sessions, American Heart Association, New Orleans, USA. November 2008
12. Køber.L et al Increased Mortality after Dronedarone Therapy for Severe Heart Failure. N.Engl J Med 2008;358:2678-87.
13. Sanofi-aventis press release 23 December 2008; data on file