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This is an NHS Suffolk document that has been adopted by the WSCCG.
Suffolk PCT Drug & Therapeutics Committee
New Medicine Report
This drug has been reviewed because it is a product that may be prescribed in primary care.
Medicine Dronedarone ( Multaq, Sanofi-Aventis )
Document status Agreed at Suffolk PCT Drug and Therapeutics Committee
meeting on May 14 th^ 2009.
Date of last revision 28 th^ July 2009
Traffic light decision Red – Hospital Only
Prescribers rating 5 – Judgement Reserved
Mechanism of action Dronedarone is a new multi-channel blocking anti-
arrhythmic compound, which is a benzofuran derivative,
structurally similar to amiodarone. The structure of
dronedarone has several key modifications compared to
amiodarone, including removal of the iodine radical and
the addition of a methane sulfonyl radical. This is believed
to decrease the lipophilicty of dronedarone. As a result it
has a shorter half life of 27 – 31 hours (the half life of
amiodarone is usually of the order of 50 days).
Dronedarone works by prolonging the action potential
duration in the atria and ventricles. The mechanism by
which dronedarone exerts its effect is through the inhibition
of multiple potassium and sodium channels, which results
in the blockage of most of the outward repolarising
potassium currents and inward depolarizing sodium
currents. Further more, dronedarone acts as a calcium
antagonist and exerts a non-competitive anti-adrenergic
action. This results in prolonged action potentials and
refractoriness, which is a class effect.
Proposed indication A license application was submitted to the European
regulatory authority in June 2008, for the use of
dronedarone to reduce cardiovascular hospitalisation or
death in patients with a history of, or with current, atrial
fibrillation or atrial flutter.
Dosage 400mg twice daily
Treatment alternatives Amiodarone, sotalalol, verapamil (see below).
Place in therapy The NICE clinical guideline on the management of atrial
fibrillation recommends a rate control strategy for groups
such as older people with persistent AF, patients with
coronary artery disease and or those who are unsuitable
for cardioversion. Beta blockers (such as sotalol) or rate
limiting calcium channel blockers (such as verapamil) are
recommended as first line monotherapy in patients who
need rate control for persistent or permanent atrial
fibrillation. Digoxin is an option for predominantly
sedentary patients with permanent AF. A rhythm control
strategy is preferred in younger patients and for those with
congestive heart failure. In patients with structural heart
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Centre for Suffolk PCT
disease, amiodarone is the drug of choice for those for
whom cardioversion is indicated.
Atrial flutter may also be managed by controlling rate by
administering drugs that act on the AV node to slow
conduction to the ventricles. Rate control is similar to that
in atrial fibrillation, and may be achieved by the use of IV
beta blockers, calcium channel antagonists and digoxin.
Dronedarone may be an alternative to amiodarone in
patients intolerant or unresponsive to it.
Future alternatives None known
Evidence for use 7 trials (6 fully published, two combined into one
publication). The published trials are against placebo. The
6 month active comparator trial with amiodarone is yet to
be published.
Statistical significance vs. placebo has been established in
the published clinical trials so far. Dronedarone reduced
the incidence of hospitalisation due to cardiovascular
events or death in patients with atrial fibrillation in one
study (3).
Details of the trials are given in appendix 1.
NNT Trial (reference) NNT
EURIDIS ADONIS
EURIDIS/ADONIS (2)
ATHENA (3) 13
Cautions / side effects In the EURIDIS/ADONIS trials (2), most adverse events
(e.g. nausea, diarrhoea) occurred in similar proportions of
dronedarone and placebo patients. However there were
statistically significant differences in elevations of serum
creatinine (2.4% dronedarone patients vs. 0.2% placebo
patients) and the development of hyperthyroidism (14.1%
placebo vs. 8.4% dronedarone). More patients taking
dronedarone than placebo discontinued treatment early
(17.9% vs. 14.9%).
In the ATHENA trial (3) adverse events occurring
significantly more frequently with dronedarone than with
placebo included bradycardia, QT interval prolongation,
diarrhoea, nausea, rash, and raised serum creatinine
levels.
Costs Not known but likely to be £56 for 28 days supply (Sanofi-
Aventis). This is forty times more expensive than generic
amiodarone.
Costs of alternatives for 28
days treatment
(BNF 57 and Drug Tariff,
April 2009)
Anti-arrhythmic (dose) Costs
Amiodarone 200mg OD £1.
(NB. Cordarone X (branded
product) = £7.
Sotalol 80mg BD £1.
Verapamil 80mg TDS £1.
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Centre for Suffolk PCT
References
1. Davy J et al. Dronedarone for the control of ventricular rate in permanent atrila
fibrillation: the Efficacy and safety of dronedaronarone for the control of
ventricular rate during atrila fibrillation (ERATO) study American Heart Journal
2. Singh B et al. Dronedarone for maintenance of sinus rhythm in atrial
fibrillation and flutter. New England Journal of Medicine 2007; 357: 987 – 99
3. Hohnoloser S et al. Effect of dronedarone on cardiovascular events in atrial
fibrillation. New England Journal of Medicine, 2009; 360 (7): 668 – 78
4. US National Institute of Health. 2008. Efficacy and Safety of dronedarone
versus amiodarone for the maintenance of sinus rhythm in patients with atrial
fibrillation. Available via www.clinicaltrials.gov/ct2/results?term=dronedarone
5. Koeber L et al. Increased mortality after dronedarone therapy for severe heart
failure. New England Journal of Medicine 2008; 358: 2678 – 87
6. Dronedarone for Atrial Fibrillation and Flutter. On the Horizon Future
Medicines. National Prescribing Centre and Wessex Drug and Medicines
Information Centre. January 2008 Monograph Number 1. 1 – 5
7. NICE Clinical Guideline 36; 2006. The management of atrial fibrillation.
8. What is atrial flutter? Medical documents. Available via
www.atrilafibrillation.org.uk/medical-professional/docs/what-is-atrila-
flutter.html
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Centre for Suffolk PCT
Appendix 1 – Summary of clinical trials
Ref No Trial Trial Design Trial Population Treatment Primary Outcomes
1 ERATO
Small 6 month phase 3 multi-national double blind placebo- controlled trial
N = 174 adults with permanent atrial fibrillation.
85 given dronedarone 89 given placebo
Dronedarone 400mg BD vs. placebo
Change in mean 24 hour ventricular rate between baseline and day 14
Dronedarone 11.0 beats per minute reduction vs. placebo 0.7 beats per minute increase. Difference 11.7 beats per minute (P< 0.0001). (NB: this statistical difference in rate did not equate to a clinically significant difference). 2 EURIDIS ADONIS
Two identical phase 3 multi-national double blind placebo controlled trials lasting 12 months reported together.
N = 1,237 adults experiencing at lease one episode of atrial fibrillation in the preceding 3 months and were in sinus rhythm for at least one hour before randomisation.
N = 612 (EURIDIS) 411 given dronedarone 201 given placebo
N = 625 (ADONIS) 417 given dronedarone 208 given placebo
Dronedarone 400mg BD vs. placebo.
Time from randomisation to first documented atrial fibrillation/atrial flutter recurrence.
Statistical significance vs. placebo was established.
96 days with dronedarone vs. 41 days with placebo (P = 0.01)
158 days with dronedarone vs. 59 days with placebo (P = 0.002)
ATHENA
Randomised phase 3 placebo controlled international multi- centre trial.
N = 4,628 adults aged 70 or over with risk factors and 75 or over with or without risk factors with a history of paroxysmal or persistent atrial fibrillation or flutter.
Dronedarone 400mg BD vs. placebo.
First hospitalisation due to cardiovascular events or death.
Dronedarone reduced the incidence of hospitalisation due to cardiovascular events or death in patients with atrial fibrillation by 24% [Hazard Ratio (HR) 0.76; CI 0.69-0.84; P<0.001].
4 DIONYSOS
Randomised, double- blind 6 month trial has been completed but not yet published.
N = 504 adults Dronedarone 400mg BD vs. amiodarone 600mg OD for 28 days then 200mg OD thereafter
Treatment failure, defined as recurrence of atrial fibrillation or withdrawal due to intolerance or lack of effectiveness.
Results not yet available.
Grids used to assist the Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications
For many years scientists have recognised two types of research:
- Primary: original studies, based on observation or experimentation on subjects.
- Secondary: reviews of published research, drawing together the findings of two or more primary studies.
In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this;
Rank: Methodology Description
1 Systematic reviews and meta- analyses
Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality.
Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis.
Both are sometimes called "overviews."
2 Randomised controlled trials
(finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals)
Individuals are randomly allocated to a control group and a group who receive a specific intervention. Otherwise the two groups are identical for any significant variables. They are followed up for specific end points.
3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes.
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Centre for Suffolk PCT
4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups.
5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time
6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series
7 Expert opinion A consensus of experience from the good and the great.
8 Anecdotal Something a bloke told you after a meeting or in the bar.
Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008
To Decide if a Medication Is To Be Used In Suffolk
Criterion to be measured Tends^ to^ poor^2 Medium^4 Tends
to good Quality of evidence in the papers reviewed 7 - 8 5 - 6 3 - 4 2 1 Magnitude of effect inferred from trials reviewed Low Medium x High Are trial end-points surrogate markers or clinical outcomes? Clinical outcomes Clinical usefulness of trial end-points x Known Side Effect Profile High Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions Poor Medium Good etc) NNT High Medium x Low Comparison Of Effectiveness With Other Medicines In Use For The Same Condition
Poor? Medium Good
Severity of Condition to be Treated Trivial Medium Severe Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration)
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Centre for Suffolk PCT
To Decide Where A Medication Is To Be Used In Suffolk
Criterion Red Amber Green D Green Skills of the (^) Experience Of The Condition Specific Specific Specific General prescriber Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General
Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy
References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14:172- (^1) Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 and Appendix 2
