Atnial Fibrillation Rate and Rhythm: Whar's on rhe Horizonl

Atdal fibrillation (AF) posss a significant burden in terms of
hospitalisation and mortaliry. The disease affecrs almost 400,000
people in Australia, a {igure that coilld double in the next 2Q years
as the popuiation ages. Unfortunately, current medications {or the
pharmacological reversion of AF are either lneffective or have side
*ffects that fimit rheir use. Treatments have also tended to address
either rate or rhythm control in AF, rather rhan both of these
important goals.
There has been no new drug available for AF in Australia for
20_ years. This has creared a c6nsiderable unme( need {or a new
effecdve and safe treatment. Recently, however, there have been
published data on a new compound, dronedarone, which is a
chemical derivativeof amiodarone. These chemical alterations have
inferred a number of key pcints of differentiation from amiadarone
('Iable l), which although considered effective is underused owing
to its p.oor tolerability profile. The following summarises key findings
from clinical trials with dronedarone.
The EURtDIS and ADONIS trials
These two muhicentre, double-blind. randomised trials were
identical in design iiar a difference in their study locations. EURIDIS
was conducted in Furope while ADOlrJlS was conducted in the
United States, Canada, Australia, South Africa and Argentina.
The trials evaluated the efflcacy of dronedarone {400 mg twice
dailyi compared with placebo, with a primary end pJint of
time to firsr recurrenee of atrial fibrillation cr flutter. Both trials
showed a significant and consistent reduction in {irst recurrence of
atrial fibrillation,/fluner {tURlDl$; p=0.0138: ADONIS; p=0.00 l7)
compared with placebo. Dronedarone also significanrly reduced
ventricular rate {p<0.0001) and the secondary endpoint af rime
to ali cause ho,spitalisation or death was shown to be significantly
reduced {p=0.0i) versus placebo.
The ANDR,CIMEDA trial
This studywas designed to assessthe potential benefitofdronedarone
(400 mg twice daily) in reducing martality and CHF hospiralisarions
in patients with severe heart failure, rather rhan in atrial fibriliation,
compared with placebo" Patients enrolled were those hospitalised
with symptomatic heart failure and severe ieft ventricular systolic
dysfunction t<35%).
The study was prematurely rerminated for excess monality seen in
the dronedarone group. During a median follow-up af 7 months,
25 patients in rhe dronedarone group {8.1%} and !2 parientc in th€
placebo graup {3.8%) died {HR; 2.13:95% Cl, |.07-4.25; P=0.03}.
This excess in mortalicy was predominantly related to worsening of
heart faiiure.
The ATHENA trial
The ATHEITIA study was conducted in padenrs with arrial fibrillarion
and is the largest antiarrhythmic drug rrial ever conducted, with
a tatal of 4628 patients wirh Ai who had addrtional risk factors
for death, randomised ro dronedarone (400 mg twice a day) or
placebo. The primary ourcome was rhe first hospiralisation due to
cardiovascular events or dearh.
At a mean follow-up of 2l^months, the study produced starisrically
significant results in the primary (Figure l) and the majority of
its secondary endpoints. A beneficial effect was also' seerr iri ail
subgroups regardless of gender. renal failure, cardiovascular disease
or concurrenr treatmenrs. Sub-analyses of rhe ATHENA dara also
showed a srarisrically significant reduction in annual rates of l)
srroke;7) stroke or TIA; 3) stroke, ACS or CV dearh; and 4) stroke,
ACS or all-cause death.
In terms of.adverse events, QT-interval prcrlongation, diarhoea
and reduced creatine excretion were seen more regulariy with
dronedarone. The later adverse event is an imporuant consideration
as physicians ffia/ stop antihypertensive treatrnent on the
presumption thar increased creatinine levels indicare renal failure,
without considerrng normal urea paramerers. This may place rhe
patient at increased risk of cardiovascular evenrs.

Drug Froperries Mortality Benefit in AF Safety Pro{ile

AMIODARONE
* Highly lipophilic * Not demonstrated* (trend to increased - Pulmonary adverse events
- '/z-life:59 days mortality in AF srudies) * Thyroid adverse events
* 3V"/o iodine by weight "studies were not designed and/ ar powered - Hepatic toxicities
* Numerous drug-to-drug interactions to demonstrate an effect on mortality.
a^-^^-l J^^^,:L-
- LU' I rsdr ucP9srLS
* Optic neuroparhy
- Skin discolouration
DRONEDARONE
* th-life'.24 hours
- Significant risk reduction in CV death - Very low risk of torsade de pointes
* No iodine moiety * Significant risk reduction for * No evidence of amiodarone-like organ
- l'lethane sulfonyl group arrhythmic death toxicity (thyroid, pulmonary hepatic, erc)
reduces lipophilicity * Increased rate of transienr
Gl adverse events

Table l" Key differences between dronedarone and amiodarone

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