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By Gemma Robinson, DipClinPharm,MRPharmS, and Sotiris Antoniou, MSc,MRPharmS

Hopes had been high during thedevelopment of dronedarone thatthe drug (a new class III

antiarrhythmic) would have the therapeuticpotential to replace amiodarone in clinicalpractice. Amiodarone has long been acommonly prescribed antiarrhythmicmedicine, with exceptional efficacy insuppressing recurrent episodes of atrialfibrillation (AF).1,2 Unfortunately,amiodarone’s toxicity profile drasticallylimits its use.2

Dronedarone is a structural analogue ofamiodarone lacking the iodine moietyassociated with amiodarone’s more severeside effects. Compared with amiodarone,dronedarone also has a reducedlipophilicity translating to a smaller volumeof distribution and less accumulation.1,3

Studies have shown that dronedarone doesshare amiodarone’s low proarrhythmicpotential2 and is generally well tolerated.

Nevertheless, dronedarone has not beenshown to be as effective as amiodarone, orindeed many of the other commonly usedantiarrhythmic medicines.2,4 This reviewsets out what dronedarone’s role will be inthe treatment of AF in clinical practice.

Atrial fibrillationAF is a tachyarrhythmia resulting from thechaotic generation of electrical signalswithin the atria, which leads to an irregularrhythm with poorly controlled rapidventricular rate. The long-term consequences of AF include impairedhaemodynamic function of the heart, alarge reduction in cardiac output and

by delayed impulses since the adjacentmyocardium remains refractory.7

Amiodarone use is greatly limited due toits numerous and severe side effects,including pulmonary, hepatic and thyroidtoxicities. Dronedarone is structurallysimilar to amiodarone, but it lacks theiodine moiety associated with amiodarone’spoor safety profile.1

Data from the DIONYSOS trial2 suggestthat dronedarone may have an improvedsafety profile when compared withamiodarone mainly driven by fewer thyroidand neurologic events. Dronedarone hasalso been associated with less bradycardiaand QTc-interval prolongation thanamiodarone, making it a desirablealternative.2

Evidence baseBox 1 summarises the evidence fromclinical trials of dronedarone (p335).

thrombogenesis leading to an increased riskof stroke.5

Historically the ultimate goal of AFtreatment has been the termination of AFand subsequent maintenance of sinusrhythm (commonly known as rhythmcontrol). The other strategy involvescontrolling ventricular rate using medicinessuch as beta-blockers and rate-limitingcalcium channel blockers (rate control).

However, the AFFIRM trial6

demonstrated no difference in overallmortality between patients treated usingrate control and those treated with arhythm-control strategy. In general,medicines used for rhythm control areassociated with substantial side effects,including proarrhythmia, bradycardia andheart block, as well as systemic toxicities5

(the latter is especially true of amiodarone). Addition of dronedarone to this group

of drugs is therefore welcomed and,although dronedarone is unlikely toreplace amiodarone completely in clinicalpractice, it will unquestionably have aplace in therapy.

Treatment with dronedaroneThe basis of drug therapy for AF lies in themanipulation of the cardiac actionpotential (illustrated in Figure 1), hencedrugs are classified on the basis of theirprimary mechanism of action and theireffects on the action potential.

Class III agents such as amiodarone anddronedarone exert their effect primarily byblocking potassium channels involved inphase 3 of the action potential, prolongingthe refractory period and delayingrepolarisation in myocytes. Thisconsequently prevents re-excitation of cells

Medicines used to treat atrial fibrillation can cause various side effects. Dronedarone, the most recentantiarrhythmic drug to become available, is well tolerated. This article looks at its place in therapy

Dronedarone

Figure 1: Phases of cardiac muscle cellaction potential and effect of dronedarone

Gemma Robinson is specialist cardiacpharmacist and Sotiris Antoniou isprincipal cardiac pharmacist, both atBarts and The London NHS Trust. E: sotiris.antoniou@bartsandthelondon.nhs.uk

VERDICTAntiarrhythmic treatment options for patients with atrial fibrillation are limited and anantiarrhythmic drug that can control symptoms with improved tolerability overamiodarone is a welcome addition.

Dronedarone, however, has limited ability to cardiovert patients to sinus rhythm andshould be reserved for the maintenance of sinus rhythm in patients who have previouslybeen cardioverted and for the control of ventricular rate. Because dronedarone is notproarrhythmic and it also lacks the non-cardiac side effects seen with otherantiarrhythmics, it is an attractive second-line option in certain pre-specified patient groups.

Phase 4–90mVResting potential

Phase 1 +10mV

Phase 0Sodium entersthe cell —depolarisation

Phase 2Calcium enters thecell — initiationof contraction

Phase 3Potassium exitsthe cell —repolarisation

Phase 0 Initial rapid depolarisation due to fast sodium channelsPhase 1 Early fast repolarisationPhase 2 Prolonged depolarisation plateau due to slow calcium influxPhase 3 Repolarisation due to closing of calcium channels and

potassium effluxPhase 4 Resting membrane potential is restored

Dronedarone prolonging phase 3 of the action potential

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The EURIDIS and ADONIS trialsdemonstrated that dronedarone is superiorto placebo in preventing recurrent AF andis also effective in controlling ventricularrate.8 Dronedarone reduced the likelihoodof recurrence of AF at one year by 25%when compared with placebo (P<0.001).

In the ATHENA study, dronedaroneprolonged the mean time to AF recurrence in patients who were in sinusrhythm at baseline to 737 days comparedwith 498 days in the placebo arm(P<0.001).9

Dronedarone has been compared withamiodarone (DIONYSOS) in terms ofefficacy and safety in patients whounderwent electrical cardioversion. Theprimary composite outcome of firstincidence of either recurrence of AF orpremature study discontinuation because of intolerance or lack of efficacy occurredin 75.5% of the dronedarone group and58.8% of the amiodarone group (hazardratio 1.59, 95% confidence interval1.28–1.98; P<0.0001). This differenceoccurred mainly because of the higherincidence of recurrence of atrial fibrillation in the dronedarone group thanin the amiodarone group (63.5% and42.0%, respectively; no P value stated).2

The main safety endpoint was definedas the incidence of thyroid, hepatic,pulmonary, neurological, skin, eye orgastrointestinal-specific events, or earlystudy drug discontinuation after anyadverse event. This endpoint occurred in39.3% of the dronedarone group after 12months of treatment compared with 44.5%of the amiodarone group (hazard ratio 0.80,CI 0.60–1.07).2 Dronedarone was associatedwith lower incidences of thyroiddysfunction, significant bradycardia andeffects on the central nervous system.

Place in therapyEvidence from trials has demonstrated thatdronedarone’s ability to terminate anepisode of AF is negligible, especially incomparison with other antiarrhythmic

TRIAL DETAILS

EURIDIS andADONIS trials(n=1,237, 12-monthfollow-up)8

Examined dronedarone’s ability to maintain patients in sinus rhythm. Eitherdronedarone or placebo were given in addition to standard first-line therapy.Results showed that fewer people in the dronedarone arm had atrial fibrillation(AF) recurrence at 12 months than in the placebo group. The combined trialdata showed that dronedarone significantly reduced the rate of hospitaladmission or death. The median time to AF recurrence was 116 days in thedronedarone group and 53 days in the placebo group. In the dronedaronegroup, the mean ventricular rate during the first adjudicated AF recurrence was103 beats/min, compared with 117 beats/min in the placebo group

ATHENA trial(n=4,628, mean follow-up21 months)9

Either dronedarone or placebo were given in addition to standard first-linetherapy. The study included people with paroxysmal or persistent AF or atrialflutter with additional risk factors. The primary outcome was a composite offirst unplanned hospital admission because of a cardiovascular event and deathbefore hospital admission. This occurred less frequently in the dronedaronegroup (31.9% versus 39.4%) and results were mainly powered by data on firsthospital admission not death before hospital admission. There was no significantdifference in all-cause mortality between the dronedarone and placebo groups;however, there were significantly fewer deaths from cardiovascular causes inthe dronedarone group than in the placebo group. A post-hoc analysis reportedthat dronedarone was associated with a reduction in all-cause mortalitycompared with placebo in people with a CHADS2 score of 4 or higher

DIONYSOS trial(n=504, 6-monthfollow-up)2

A head-to-head study comparing dronedarone with amiodarone. The primarycomposite outcome of first incidence of either recurrence of AF or prematurestudy discontinuation because of intolerance or lack of efficacy, occurred in75.5% of the dronedarone group and 58.8% of the amiodarone group. Thisdifference was mainly because of the higher incidence of recurrence of AF inthe dronedarone group than in the amiodarone group. Dronedarone wasassociated with lower incidences of adverse drug reactions, including thyroiddysfunction, significant bradycardia and effects on the central nervous system

Box1: Summary of clinical evidence

drugs.4,10 Dronedarone will, however, have aplace in the maintenance of sinus rhythm,once patients have been cardioverted tosinus rhythm, and for the control ofventricular rate.

In the UK, dronedarone is licensed foruse in clinically stable patients with a historyof, or current, non-permanent AF to preventrecurrence or to lower ventricular rate.11

Guidance from the National Institute forHealth and Clinical Excellence hasrecommended the use of dronedarone forpatients with one or more additional riskfactors (see Box 2, p336).12 Theserecommendations were based largely onthe ATHENA trial — a post-hoc analysisof which reported that dronedarone was

associated with a statistically significantreduction in all-cause mortality comparedwith placebo in people who score 4 ormore according to CHADS2 (used to assessstroke risk in patients with AF).9

Although dronedarone has been shownto be effective for the maintenance of sinusrhythm when compared with placebo,8,9 itshould be noted that other agents such asflecainide, amiodarone, sotalol andpropafenone are thought to be moreeffective for this indication, although nohead-to-head studies have beencompleted.4 Nevertheless, the adverseeffects of these agents (eg, proarrhythmia,bradycardia, heart block), as well as thesystemic toxicity seen with amiodarone,limit their use. Dronedarone, therefore, canbe viewed as an agent with a lower efficacy,but improved safety over other agents.

The European Society of Cardiologyguidelines for the treatment of AF discussthe concept of safety over efficacy in theselection of agents for the treatment of AFand conclude that “safety rather thanefficacy considerations should primarilyguide the choice of antiarrhythmic agent”.5

Potential recipients of dronedarone mayinclude patients who are unable to tolerateother antiarrhythmic drugs, in particular

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Dronedarone can help to maintain sinus rhythm

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amiodarone. This may be an appealingtreatment option particularly for youngerpatients who require antiarrhythmictherapy over a longer period. As a patientgroup, AF sufferers are proactive and valuechoices regarding their therapy. It isprobable that patients may requestdronedarone from prescribers,acknowledging its lower efficacy butpreferring its presumed improvedtolerability and safety profile.The reduced lipophilicity of

dronedarone results in a smaller volume ofdistribution and an elimination half-life of24 hours (in contrast to amiodarone’s half-life of 26–107 days).3

The rapid onset of dronedarone alongwith its small volume of distribution meansno loading dose is necessary — a potentialbenefit over amiodarone. This may makeprescribing less complicated and reducethe potential for dosing errors.3

Important safety issues From the trials conducted to date,gastrointestinal disorders were the mostcommon reason for patients discontinuingdronedarone. Other less common sideeffects include rash, bradycardia, andprolonged QTc interval.2

Renal effects A 10–15% increase inplasma creatinine has been observed inmore than 10% of patients treated withdronedarone.11,13 The increase occurs earlyafter starting treatment and reaches aplateau after seven days, the point at whicha plasma creatinine should be measured. Ifan increase in creatinine is observed, thisvalue should be used as the new referencebaseline (ie, taking into account that this isto be expected with dronedarone).11

Dronedarone is contraindicated in patientswith creatinine clearance <30ml/min.11

Heart failure The use of dronedarone inunstable patients with New York HeartAssociation class III and IV heart failure iscontraindicated. Because of limitedexperience in stable patients with recent(one to three months) NYHA class IIIheart failure or with left-ventricularejection fraction <35%, the use ofdronedarone is not recommended;therefore, amiodarone is likely to remainthe drug of choice in this patient group.11,12

Interactions Dronedarone is primarilymetabolised by cytochrome P450 3A4 andalso inhibits CYP2D6. It is a potent P-glycoprotein inhibitor. Clinicallysignificant interactions include:11

� Warfarin — exposure to warfarinmay be increased so closermonitoring is recommended

� Statins — increased exposure tostatins means lower starting dosesand closer monitoring for musculartoxicity are required

� Beta-blockers — dronedarone willincrease exposure to beta-blockersmetabolised by CYP2D6; initiationat lower doses and closer monitoringare required

� Digoxin — dronedarone increasesdigoxin exposure by inhibiting P-glycoprotein transporters; digoxindose should be reduced by about50% and levels monitored closely

� Grapefruit juice and St John’swort — greatly increasedronedarone exposure soconcomitant use is contraindicated

Pharmacy inputSelection of an appropriate medicine fortreating AF should be based first on safety,tailored to what underlying heart diseasemay be present. Pharmacists involved in screening

prescriptions for dronedarone should beaware of the clinically relevant interactionsand how to manage these. Patients who aretaking statins will need regular monitoringfor signs of myopathy, particularly those onhigh-intensity statin therapy.Patients will need to be advised not to

consume grapefruit juice drinks or take StJohn’s wort due to their interaction withdronedarone.11

Pharmacists should note that around10% of patients will experience raisedserum creatinine and this is not a reason tostop therapy.11 The creatinine resultobtained seven days after startingdronedarone should be considered the new baseline creatinine level for the patient.

Box 2: What NICE recommends

The National Institute for Health and Clinical Excellence published its technologyappraisal for dronedarone in August 2010.12 It recommends the use of dronedarone as anoption for the treatment of people with non-permanent atrial fibrillation that is notcontrolled by first-line therapy (usually beta-blockers) and who have/meet at least one ofthe following:

� Hypertension requiring medicines from at least two different classes� Diabetes mellitus� Previous transient ischaemic attack, stroke or systemic embolism� Left atrial diameter of 50mm or greater� Left-ventricular ejection fraction <40%� Age 70 years or older and without unstable New York Heart Association class III or

IV heart failure

A full review of atrial fibrillation and itstreatment will be published in theNovember issue of Clinical Pharmacist.For the first time, the CLINICAL FOCUSarticles will be linked to alearning@lunch flex module, produced incollaboration with the Centre forPharmacy Postgraduate Education.

Next month in CLINICAL FOCUS

References 1 Camm JA, Savelieva I. Dronedarone: a new option in

atrial fibrillation. Future Prescriber 2009;10:24–32.

2 Heuzey J, De Ferrari GM, Radzik D, et al. Short-term,randomized, double-blind, parallel-group study toevaluate the efficacy and safety of dronedarone versusamiodarone in patients with persistent atrialfibrillation: the DIONYSOS study. Journal ofCardiovascular Electrophysiology 2010;6:597–605.

3 UKMi London New Drugs Group, APC/DTC briefingdocument: dronedarone for atrial fibrillation. April2010. www.nelm.nhs.uk/en/NeLM-Area/Evidence/Drug-Specific-Reviews/Dronedarone-for-atrial-fibrillation/?id=516672 (accessed 13 August 2010).

4 Schilling RJ. Cardioversion of atrial fibrillation: theuse of antiarrhythmic drugs. Heart 2010;96:333–8.

5 Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC2006 guidelines for the management of patients withatrial fibrillation — executive summary. EuropeanHeart Journal 2006;27:1979–2030.

6 Wyse DG, Waldo AL, DiMarco JP, et al. A comparisonof rate control and rhythm control in patients withatrial fibrillation, New England Journal of Medicine2002;347:1825–33.

7 Aaronson PI, Ward JPT. The cardiovascular system at aglance, 3rd edition. 2007. Wiley-Blackwell.

8 Singh BN, Connolly SJ, Crijns HJGM, et al.Dronedarone for maintenance of sinus rhythm in atrialfibrillation or flutter. New England Journal of Medicine2007;357:987–99.

9 Hohnloser SH Crijns HJGM, van Eickels M, et al.Effect of dronedarone on cardiovascular events inatrial fibrillation. New England Journal of Medicine2009;360:668–78.

10 Touboul P, Brugada J, Capucci A, et al. Dronedaronefor prevention of atrial fibrillation: a dose-rangingstudy. European Heart Journal 2003;24:1481–7.

11 Sanofi-aventis. Summary of product characteristics:Multaq. www.medicines.org.uk/EMC/searchresults.aspx?term=dronedarone&searchtype=QuickSearch(accessed 13 August 2010).

12 National Institute for Health and Clinical Excellence,Dronedarone for the treatment of non-permanent atrialfibrillation. August 2010. www.nice.org.uk/ta197(accessed 13 August 2010).

13 Tschuppert Y, Buclin T, Rothuizen LE, et al. Effect ofdronedarone on renal function in healthy subjects. BritishJournal of Clinical Pharmacology 2007;64:785–91.

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