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Dronedarone: review of trials and up-to-date recommendations

An article from the e-journal of the ESC Council for Cardiology Practice

Dronedarone in high-risk permanent atrial fibrillation - PALLAS - was stopped for safety reasons leaving little post - trial discussion. It concluded that dronedarone should be avoided in patients with permanent atrial fibrillation and, as previously shown, in patients with heart failure. Find a short up-to-date review of trials and summary of recommendations concerning the drug here. 

Atrial Fibrillation


Background

When the antiarrhythmic dronedarone first made its appearance in 2009, it offered great promise: its lack of iodine, compared to amiodarone, would lead to reduced toxic effects on the thyroid and other organs while proving maintained efficacy.
In a broad range of patients with paroxysmal, persistent or permanent atrial fibrillation and heart failure, the DAFNE (2), EURIDIS (3), ADONIS (3) and ERATO (4) studies, dronedarone appeared safe and showed efficacy for rhythm control. Compared with amiodarone in DIONYSOS (5) it also had a good safety profile - albeit showing less efficacy in the latter study.  
Dronedarone was then studied in a series of three large phase III studies-ATHENA (6), ANDROMEDA (7) and PALLAS (8); the latest of which found that dronedarone in permanent atrial fibrillation had a two fold increase in all-cause death, cardiovascular death, arrhythmic death, stroke, myocardial infarction, cardiovascular (CV) hospitalisation and hospitalisation for heart failure. 

ATHENA & ANDROMEDA

ATHENA (6) randomised 4629 subjects with paroxysmal or persistent atrial fibrillation. Dronaderone showed a significant reduction in its primary composite endpoint of cardiovascular hospitalisations or death from any cause (24%, p<0.001). There was a consistent positive effect seen in reductions achieved, CV death (29%, p=0.03), arrhythmic death (45%, p=0.01) although all cause mortality was not significantly reduced (16%, p=0-.18). In the permanent atrial fibrillation subgroup of patients there were trends for favourable CV outcomes (26% reduction in hospitalisation and death, 20% reduction in stroke, acute coronary syndromes and CV death). 
ANDROMEDA (7) evaluated 627 subjects with heart failure (without atrial fibrillation) as a possible other indication for this agent however the study was terminated early due to a two-fold increase in mortality (25 in the dronedarone group and 12 in the placebo group, HR=2.13; CI-1.07-4.25, p=0.03). The primary combined endpoint of all-cause mortality or hospitalisation for worsening heart failure was not significantly different between the two groups.

PALLAS

Following ATHENA, which studied subjects with paroxysmal or persistent atrial fibrillation and ANDROMEDA which studied subject with heart failure PALLAS was designed to study patients with permanent atrial fibrillation. Subjects with active decompensated heart failure were excluded. PALLAS was also halted abruptly for excess mortality. Full results were presented at the 2011 AHA scientific sessions which were also published in the New England Journal of Medicine (8). PALLAS recruited 3236 patients, and was halted at a median follow up of 3.5 months for two fold increases in the first composite primary outcome of stroke, systemic embolism, myocardial infarction or CV death (HR-2.29, C.I-134-3.94, p=0.002) and the second composite primary outcome of unplanned CV hospitalisation or death (HR-1.95, C.I= 1.45-2.64, p<0.001). All-cause death, CV death, arrhythmic death, stroke, MI, CV hospitalisation and hospitalisation for heart failure were all significantly higher in the dronedarone treated patients (Table), with a consistent hazard seen across all-predefined subgroups. The fact that 21% subjects discontinued the study drug in the dronedarone arm versus 11% in the placebo arm highlights the poor tolerance of the drug in this subset of patients. 

Such different results. What happened?

In trying to assess the reasons for the diametrically opposed results of ATHENA relative to PALLAS, some thoughts come to mind:

  1. While no previous trials like PALLAS were carried out specifically in permanent AF patients, various previous experiences with antiarrhythmic drugs such as quinidine (10), d-sotalol (11), encainide (12), moricizine (13), flecainide (14) and amiodarone (15) have shown similar adverse results. 
  2. The hints of problems seen in ANDROMEDA in patients with heart failure, may have been true after all. There does appear to be an issue, albeit not fully defined, that increased cardiovascular event rates of all types are now seen with this agent.

Practice recommendations

While one is left to wonder about what is electrophysiologically so different in permanent atrial fibrillation, the results of PALLAS reflected in the recommendations from the US Federal Drug Administration (16) and the European Medicines Agency (17) are the following:

  • Avoid dronedarone 1) in patients with permanent atrial fibrillation 2) previous amiodarone related liver toxicity 3) current symptoms or past symptoms of HF 4) left ventricular systolic dysfunction (EF <35%)*.
  • Consider dronedarone as still an option 1) for paroxysmal or persistent atrial fibrillation patients who present in sinus rhythm and are clinically stable (EMA), 2) in patients who are proposed to be cardioverted (FDA).
  • Monitor patients on dronedarone every 3 months for their heart rhythm.
  • Keep in mind that in permanent atrial fibrillation antiarrhythmic drugs carry significant risks with little benefit.
  • Focus on rate control and adequate antithrombotic therapy.

*only in FDA, in the context of Class IV NYHA heart failure.

Table 1. Cardiovascular outcomes - PALLAS

End pointDronedarone versus placebo
Hazard ratio (95% Confidence Interval)  
p-value
Co-primary end point: stroke, MI, systemic embolism, or CV death   2.29 (1.34-3.94)  0.002
Co-primary end point: death or unplanned CV hospitalisation  1.95 (1.45-2.62) <0.001
Mortality 1.94 (0.99-3.79)  0.049
CV death 2.11 (1.00-4.49) 0.046
Arrhythmic death  3.26 (1.06-10.00)  0.03
Stroke  2.32 (1.11-4.88) 0.02
HF hospitalisation  1.81 (1.10-2.99) 0.02
HF event or hospitalisation   2.16 (1.57-2.98) <0.001

References


1.Dronedarone: an amiodarone analogue.
Doggrell SA, Hancox JC.  Expert Opin Investig Drugs 2004;13(4):415-26.
2.Dronedarone for prevention of atrial fibrillation: a dose-ranging study
Touboul P, Brugada J, Capucci A, Crijns HJ, Edvardsson N, Hohnloser SH. Eur Heart J 2003;24(16):1481-7.
3.Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter.
Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, Radzik D, Aliot EM, Hohnloser SH.  N Engl J Med 2007;357(10):987-99.
4.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.
Davy JM, Herold M, Hoglund C, Timmermans A, Alings A, Radzik D, Van Kempen L.  Am Heart J 2008;156(3):527 e1-9.
5.A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study.
Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. J Cardiovasc Electrophysiol 2010;21(6):597-605.
6.Effect of dronedarone on cardiovascular events in atrial fibrillation.
Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ.  N Engl J Med 2009;360(7):668-78. 
7.Increased mortality after dronedarone therapy for severe heart failure.
Kober L, Torp-Pedersen C, McMurray JJ, Gotzsche O, Levy S, Crijns H, Amlie J, Carlsen J.  N Engl J Med 2008;358(25):2678-87.
8. Dronedarone in high-risk permanent atrial fibrillation.
Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum A, Blomstrom P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacretaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB, Heidbuchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsanyi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH.. N Engl J Med 2011;365(24):2268-76.
9.Dronedarone for atrial fibrillation have we expanded the antiarrhythmic armamentarium?
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10. A meta-analysis of randomized control trials.
Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. Circulation 1990;82(4):1106-16.
11.Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction.
Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996;348(9019):7-12.
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Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al. . The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324(12):781-8.
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15.Lessons from antiarrhythmic trials involving class III antiarrhythmic drugs

VolumeNumber:

Vol10 N°28

Notes to editor


Sameer Bansilal, MD, MS, Christopher P. Cannon MD 

TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 350 Longwood Avenue, 1st floor office suites, Boston, MA 02115, USA.

Authors disclosures: None declared. 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.