Dronedarone For Atrial Fibrillation: Unbridled Enthusiasm Or Just Another Small Step Forward?
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Credits:James A. Reiffel, M.D
corresponding Address : James A. Reiffel, M.D, Columbia University, 161 Fort Washington Ave, New York, NY 10032.
In July 2009, the federal Food and Drug Administration (FDA)
approved the marketing of dronedarone (Multaq, sanofi-aventis) for use in
patients with atrial fibrillation (AF) or flutter (AFL) [with a requirement for
a recent episode] that is paroxysmal or persistent – the latter having been
converted to sinus rhythm or with conversion planned – who have, in addition to
AF, certain “high-risk” markers for adverse outcomes that were derived from the
enrollment criteria for the landmark ATHENA trial [1]. These
markers include one or more of: age >70 yrs, hypertension, diabetes
mellitus, prior cerebrovascular accident, left atrial size of 50 mm or larger,
or LVEF <40%. Contraindications include class IV heart failure or
symptomatic heart failure with a recent decompensation; second or third degree
AV block without a functioning pacemaker; bradycardia < 50 bpm; concomitant
use of a strong CYP3A inhibitor or a QT prolonging agent that may induce
torsades de pointes; QTc Bazett interval of 500 ms or longer; or severe hepatic
impairment.
This approval was the culmination of a developmental course
that was detailed by Peter J. Zimetbaum, M.D. in his April 30, 2009 article in
the New England Journal of Medicine entitled: Dronedarone for Atrial
Fibrillation – An Odyssey [2]. In this development
process, dronedarone, an agent derived from amiodarone, with a similar but
non-identical electrophysiologic profile, but with more user-friendly
pharmacokinetics and an apparently much lower risk of toxicity – as was
summarized in Dr. Zimetbaum’s manuscript-- was first proven superior to placebo
in the suppression of atrial fibrillation in a mixed population of patients in
the EURIDIS and ADONIS trials [3]. In these trials
dronedarone reduced the rate of recurrent AF from 75% to 64%; in addition, the
ventricular rate during recurrences was reduced 12-15 bpm. The dose used was
400 mg bid – the only dose used in the pivotal trials for this agent, which is
an outcome of its dose-ranging DAFNE trial [4] in which
higher doses were poorly tolerated due mainly to diarrhea as well as appearing
less effective. The prohibition against its use in class IV heart failure or
heart failure with recent decompensation was the result of the premature
termination of the ANDROMEDA trial [5] – a mortality and
morbidity trial in patients with LVEF 35% or lower and decompensated
symptomatic heart failure – in which the trial was terminated early due to
excess mortality and hospitalization risk on the active agent as compared to
placebo. The requirement for additional cardiovascular risk markers in
addition to AF/AFL and the specific indication for dronedarone – “to reduce the
risk of cardiovascular hospitalization” in patients with AF or AFL with a
recent episode “and associated cardiovascular risk factors” was derived from
the dramatic findings in the ATHENA trial [1]. ATHENA
demonstrated, in 4628 patients with a recent episode of AF or AFL and specific
associated risk markers including those identified above, that dronedarone, as
compared to placebo, was associated with a lower risk of the composite endpoint
of death from any cause and hospitalization due to cardiovascular events. There
was a non-significant trend towards reduction of total mortality. The
reduction in cardiovascular hospitalization was largely due to a reduction in
AF/AFL events requiring hospitalization – but, of note, time to first AF
recurrence, the number of AF recurrences, and similar measures of AF burden
were not outcome events measured in this trial. The results were generally
similar in all subgroups that were assessed, including a variety of commonly
used cardiovascular drugs. Also reduced were acute coronary syndrome, and, as
shown in a post-hoc analysis, presented at the 2008 European Society of
Cardiology meetings by Dr. Hohnlosser, stroke (independent of the use of
anticoagulants).
Consequent to the approval of dronedarone, for the
indication detailed above – which is not simply for the reduction of AF/AFL
(i.e., for prolongation of the time to recurrence, the most common indication for
drugs approved for the therapy of AF/AFL) – how are physicians likely to use
this drug and what unknowns remain that may be necessary to learn in order to
ultimately use dronedarone to its fullest and most appropriate potential.
Perhaps the two major limitations at this point are the
limited duration of long-term experience with the drug and limited comparative
efficacy and tolerance/safety data. In the trials outlined in dronedarone’s
“odyssey” [2], the duration of follow up was generally 1 year
with the longest follow up for any patient approximating 3 years. Thus, while
in these trials dronedarone appeared to be free of the pulmonary, thyroid, and
other toxicities that plague the use of amiodarone, we have to recognize that longer
exposure without events will truly be required to assure us fully as to its
chronic safety profile. Recall that some of amiodarone’s toxic profile is
total dose and time exposure dependent. Secondly, we have very limited
comparative efficacy for dronedarone against other antiarrhythmic agents (AADs).
The only such data that exits is that from the DIONYSOS trial [2]
in which dronedarone and amiodarone were compared in a 500 patient trial of
only 6 months duration in which dronedarone demonstrated lower efficacy against
AF than did amiodarone, but fewer adverse effects and a lower rate of drug
withdrawal. Hence, how it might perform against other AADs either in the
suppression of AF/AFL or in a trial similar to ATHENA is unknown.
So, where does all this information leave the clinician who
now must incorporate it into his or her armamentarium? One view might be that
given the dramatic outcome events demonstrated in ATHENA, dronedarone should be
the first AAD tried in AF/AFL patients with a recent arrhythmic event and the
associated cardiovascular risk profile that is part of the indication for this
agent – it may be seen as unethical to do otherwise. Others may have less
unbridled enthusiasm preferring to await longer-term safety data than currently
exists and more comparative data than currently exists before taking such a
strong stance. Personally, I find myself somewhere in between, but leaning
towards the former and would propose that dronedarone has a role in each of the
arms of the treatment algorithm outlined in the 2006 ACC/AHA/ESC guidelines [6] as shown in the following figure that I
have developed specifically for this manuscript.
Figure 1: A suggestion for the application of dronedarone to the ACC/AHA/ESC algorithm.
Panel 1:patients with no or minimal heart disease |
Panel 2: Patients with hypertension without significant hypertrophy |
Panel 3: patients with hypertension with significant hypertrophy: here, there is no significant published data to indicate safety for the specific use of dronedarone |
Panel 4: patients with coronary artery disease |
Panel 5: patients with heart failure |
Panel 6: patients with heart failure in whom dronedarone is contraindicated |
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Hohnloser SH, Crijns HJGM, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668-678.CrossRef
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Zimetbaum PJ. Dronedarone for atrial fibrillation – an odyssey. N Engl J Med 2009; 360:1811-1813.CrossRef
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Singh BN, Connolly SJ, Crijns HJGM, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987-999.CrossRef
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Touboul P, Brugada J, Capucci A. et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J. 2003;24:1481-1487.CrossRef
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Kober L, Torp-Pedersen C, McMurray JJV, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678-2687.CrossRef
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Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Eur Heart J. 2006; 27:1979-2030.
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