National Horizon Scanning Centre. Dronedarone (Multaq) for atrial fibrillation and atrial flutter. December 2007

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1 Dronedarone (Multaq) for atrial fibrillation and atrial flutter December 2007 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The Research Programme is part of the National Institute for Health Research

2 Dronedarone (Multaq) for atrial fibrillation and atrial flutter Target group Paroxysmal, persistent and permanent atrial fibrillation (AF) and atrial flutter. Technology description Dronedarone (Multaq), a multichannel antagonist (potassium, sodium and calcium channel blocker with antiadrenergic properties), is chemically related to amiodarone and is in phase III trials as a class III antiarrhythmic agent for the treatment of atrial fibrillation and atrial flutter. In phase III trials dronedarone is administered orally twice a day at a dose of 400mg. Dronedarone may increase mortality in patients with heart failure and has not been extensively studied in other populations with structural heart disease, therefore its use may be limited to the treatment of AF in patients without structural disease until the results of the ATHENA study are available 1. Innovation and/or advantages Dronedarone is reported to have fewer adverse effects than amiodarone, a licensed multichannel blocker antiarrhythmic agent. Developer Sanofi-Aventis. Place of use Home care e.g. home dialysis Secondary care e.g. general, non-specialist hospital General public e.g. over the counter Community or residential care e.g. district nurses, physio Tertiary care e.g. highly specialist services or hospital Other: Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care Availability, launch or marketing dates, and licensing plans: Sanofi-Aventis received a non-approvable letter from the US FDA for dronedarone in the treatment of atrial fibrillation/atrial flutter in August 2006 and subsequently withdrew its European application for Marketing Authorisation in September The company expect to re-apply for approval to both the EMEA and the FDA in Q2 2008, based on results from the ongoing ATHENA study. NHS or Government priority area: This topic is relevant to the National Service Frameworks for Coronary Heart Disease and Older People. Relevant guidance NICE clinical guideline. Atrial fibrillation (expected review date June 2010). SIGN clinical guideline. Cardiac arrhythmias in coronary heart disease NLH Guidance. Atrial Fibrillation American College of Cardiology/American Heart Association/European Society of Cardiology guidelines for the management of patients with atrial fibrillation NICE appraisals completed: o Implantable cardioverter defibrillators for arrhythmias o Bradycardia dual chamber pacemakers

3 NICE appraisals in development: o Atrial fibrillation idraparinux sodium. Currently suspended as the manufacturer of idraparinux sodium has advised NICE that the regulatory strategy in relation to this product is not finalised. Completed NICE Interventional Procedures: o Cryoablation for atrial fibrillation in association with other cardiac surgery. o High intensity focused ultrasound ablation for atrial fibrillation as an associated procedure with other cardiac surgery. o Microwave ablation for atrial fibrillation in association with other cardiac surgery o Percutaneous occlusion of left atrial appendage. o Percutaneous radiofrequency catheter ablation for atrial fibrillation. o Radiofrequency ablation for atrial fibrillation in association with other cardiac surgery. Clinical need and burden of disease AF is the commonest sustained cardiac arrhythmia 1. A closely related atrial arrhythmia is atrial flutter. Some patients have both atrial flutter and atrial fibrillation and both arrhythmias are associated with a increased risk of thrombus formation and thromboembolism including ischaemic stroke. The prevalence of AF roughly doubles with each advancing decade of age, from 0.5% at age years to almost 9% at age years. In the UK, more than 46,000 new cases of AF are diagnosed each year. In UK hospitals, 3-6% of patients admitted with acute medical conditions have AF. Men are more often found to have AF than women. Atrial flutter is much less common than AF and the exact incidence is not known. Prevalence increases with age, it is more common in men than women and is common during the first week after open-heart surgery. Existing comparators and treatments Rate control options include: o beta-blockers or rate-limiting calcium-channel blockers (diltiazem or verapamil) are the preferred initial monotherapy o digoxin monotherapy especially if there is also heart failure o electrophysiological or surgical interventions for rate and rhythm control. If monotherapy is inadequate a beta-blocker or a rate-limiting calcium-channel blocker is given with digoxin. Rhythm control options include: o amiodarone (class III antiarrhythmic agent) - requires specialist initiation and it has a high incidence of adverse effects. Approximately 914,000 prescription items were dispensed in the community for amiodarone in England in Efficacy and safety Trial name EURIDIS, NCT phase III ADONIS, NCT phase III or code Sponsor Sanofi-Aventis Sanofi-Aventis Status Published 9 Published 9 Location Europe (12 countries) USA, Canada, Australia, South Africa, and Argentina 3

4 Design Placebo-controlled, double-blind Placebo-controlled, double-blind Participants in trial n= 612; at least one episode of AF in preceding 3 months; in sinus rhythm for at least an hour before randomisation. Randomised to either 400mg dronedarone twice daily or placebo. n= 625; at least one episode of AF in preceding 3 months; in sinus rhythm for at least an hour before randomisation. Randomised to either 400mg dronedarone twice daily or placebo. Follow-up 12 months 12 months Primary Time to recurrence of AF Time to recurrence of AF outcome Secondary outcomes Symptoms related to AF; mean ventricular rate during the first recurrence Symptoms related to AF; mean ventricular rate during the first recurrence Key results Adverse Effects Median time to recurrence of AF was 96 days for dronedarone vs. 41 days for placebo. At 12 months, 67.1% of dronedarone and 77.5% of placebo group had a recurrence of AF (HR 0.78; 95% CI ; p=0.01). 37.1% of dronedarone and 47.5% in placebo group had symptomatic recurrences (p=0.006). Median time to recurrence of AF was 158 days for dronedarone vs. 59 days for placebo. At 12 months, 61.1% of dronedarone and 72.8% of placebo group had a recurrence of AF (HR 0.73; 95% CI ; p=0.002). 38.3% of dronedarone group and 44.5% in placebo group had symptomatic recurrences (p=0.02). Ventricular arrhythmias occurred infrequently in both study groups; no episodes of torsades de pointes were reported. Elevated serum creatinine for dronedarone vs. placebo 2.4% vs. 0.2%, p=0.004 (EURIDIS and ADONIS data combined) 9 Trial name ANDROMEDA, NCT ERATO - phase III or code phase III Sponsor Sanofi-Aventis Status TERMINATED in 2003 following Data Published in abstract 10 Safety Monitoring Board s recommendation. Location Europe - Design Double-blind, placebo-controlled - Participants in trial Follow-up Primary outcome Secondary outcomes Key results Adverse effects n=1,000 (planned); n=627 (actual). High risk patients with congestive heart failure and ventricular dysfunction. 400mg or matching placebo. Mean duration of follow-up (±SD) at study cessation 70.4 (±43.9) days. Death, hospitalisation for acute cardiovascular reasons Death, arrhythmic/sudden death Worsening heart failure was the primary cause of death in 40% of the patients in the dronedarone group and 17% of the patients in the placebo group. Additional follow-up data collected 6 months after the trial termination revealed that mortality risk was similar between the two groups 7. n=174. Randomised to 400mg dronedarone twice a day or placebo 14 days Mean 24-hour ventricular rate during exercise Mean ventricular rate during exercise and tolerability Dronedarone was associated with a reduction in mean 24-hour ventricular rate of 11.7 beats per minute compared to placebo. During maximal exercise on day 14 the mean ventricular rhythm was 27.4 beats per minute lower with dronedarone (p<0.001). - No torsades de pointes; no significant difference in serious adverse events or deaths compared to placebo 4

5 Trial name DIONYSOS, NCT ; phase III ATHENA, NCT ; phase III or code Sponsor Sanofi-Aventis Sanofi-Aventis Status Ongoing (started June 2007) 11 Ongoing (started June 2005) completed recruitment 10 Location World Multinational Design Double-blind, active control Double-blind, randomised Participants in trial n=472; documented AF for more than 72 hours; cardioversion and antiarrhythmic treatment is indicated Randomised to dronedarone (400mg twice a day) versus amiodarone (600mg daily for 28 days, then 200mg daily thereafter) n=4,628; aged 70 years or older; AF/atrial flutter within the last 6 months; Dronedarone (400 mg twice a day) versus placebo (ratio 1:1) Follow-up - Mean follow-up duration of 1.75 years Primary Recurrence of atrial fibrillation or Combined endpoint of cardiovascular outcome discontinuation for intolerance or lack of hospitalisation and death Secondary outcomes Expected reporting date efficacy Occurrence of thyroid, hepatic, pulmonary, neurological, skin, eye or gastrointestinal specific events Not known Death of any cause, cardiovascular death, cardiovascular hospitalisation and noncardiovascular hospitalisation Not known Estimated cost and cost impact The unit cost of dronedarone is unknown. Amiodarone costs approximately 32 per annum for a maintenance dose of 200mg/day a. Potential or intended impact speculative Patients Reduced morbidity Quicker, earlier or more accurate diagnosis or identification of disease Reduced mortality or increased survival Other: Improved quality of life for patients and/or carers Non identified Services Increased use Service reorganisation required Staff or training required Decreased use Other: Non identified Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Savings: Other: cost unknown References a Costs from BNF no

6 1 Dale KM & White CM. Dronedarone: an amiodarone analog for the treatment of atrial fibrillation and atrial flutter. The Annals of Pharmacotherapy 2007:41; National Institute of Health and Clinical Excellence. Atrial Fibrillation. National clinical guideline for management in primary and secondary care. June Scottish Intercollegiate Guidelines Network (SIGN). Cardiac arrythmias in coronary heart disease. No. 94. February National Library for Health. Guidance. Atrial Fibrillation. January Accessed 9/11/ Fluster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation 2006;114:e257-e National Institute for Health and Clinical Excellence. Implantable cardioverter defibrillators for arrhythmias. Technology Appraisal 95. January National Institute for Health and Clinical Excellence. Bradycardia dual chamber pacemakers. Technology Appraisal 88. February Data from Prescription Cost Analysis Data: Copyright, The Information Centre, Prescribing Support Unit. 9 Singh BN, Conolly SJ, Crijns HJGM et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation of flutter. NEJM 2007:357; Davy J-M, Singh BN, Hohnloser SH. The efficacy and safety of dronedarone as a novel rate control agent for the treatment of atrial fibrillation. European Society of Cardiology. September P ClinicalTrials.gov accessed on 9/11/2007 The National Institute for Health Research Research Programme is funded by the Department of Health. The views expressed in this publication are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health The, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0)