Evidence Based Review Article
The Journal of Informed Pharmacotherapy
Oral Amiodarone for Prevention of Atrial
Fibrillation after Open Heart Surgery: Does a Fist Beat Scissors?
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Reviewer: Richard S. Slavik, B.Sc.(Pharm.), Pharm.D.
Reviewer's email address: firstname.lastname@example.org
Reviewer's profession/specialty: Pharmacotherapeutic
Giri S, White CM, Dunn AB, Felton K, Freeman-Bosco L, Reddy P,
Tsikouris JP, Wilcox HA, Kluger J. Oral amiodarone for prevention of atrial
fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial
(AFIST): a randomised placebo-controlled trial. Lancet 2001;357:830-6.
Overall Study Question
The AFIST trial was a
prospective, randomized, placebo-controlled study undertaken in a 600-bed
tertiary care center to assess the safety and efficacy of a brief oral
amiodarone regimen for prevention of post cardiac surgery atrial fibrillation
(AF) in patients 60 years and older already receiving beta
Patients were included if they were at least 60 years old, in normal sinus
rhythm (NSR), hemodynamically stable (SBP >90 mm Hg), had a normal baseline
QTc < 440 msec, and were available at least 1 day prior to scheduled
cardiopulmonary bypass surgery. Patients were excluded if they had chronic AF,
myocardial infarction within the past 3 weeks, HR <45 bpm, advanced heart
block, automatic implantable defibrillator, a history of amiodarone toxicity,
untreated thyroid disease, hepatic transaminases greater than four times normal,
and interacting drugs. Patients were randomized to receive either a slow or fast
oral loading regimen of amiodarone or matching placebo prior to surgery and
continued for four days post-op. The primary outcome was the incidence of any
post-operative AF lasting longer than 5 minutes during the 30-day follow-up.
Are the Results of the Study
1. Was assignment of patients randomized?
Yes. During a 14-month period, 1
430 patients undergoing angiography for
ischemic heart or valvular disease were screened using consecutive sampling. A
computer-generated randomization table was used to assign patients to either a
slow load or fast load group with each group stratified by presence or absence
of valvular surgery. The slow load group (>=
5 days before surgery) received
oral amiodarone 200 mg daily for 5 days before surgery, 400 mg twice daily on
the day of surgery, and 400 mg twice daily on post-op days 1-4 or matching
placebo. The fast load group (<5 but >1 day before surgery) received
400 mg four times daily for 1 day, 600 mg twice daily on the day of surgery,
and 400 mg twice daily on post-op days 1-4 or matching placebo.
2. Were all patients who entered the trial properly accounted for and
attributed at its conclusion?
Yes. One thousand four hundred and thirty patients were screened and 379
patients met the study criteria. Reasons for ineligibility were provided. Of
the 379 eligible patients, 220 were randomized – 120 in the amiodarone group
and 100 in the placebo group. The primary outcome was analyzed using the
intention to treat principle and no patients were lost to follow-up. Drug
withdrawal in the amiodarone and placebo groups was 6.7% and 5%, and overall
in-hospital mortality and 30-day mortality rates were 2.3% and 3.6%.
3. Were patients, their clinicians, and study personnel 'blind' to
- Yes. The randomization schedule was sealed in opaque envelopes and kept in
the central pharmacy. Only the investigational pharmacist and the unmarked
study administrator had knowledge of treatment group allocation, and neither
had patient contact nor extracted data. All treatment regimens were
double-blinded and an identical matching placebo was used.
4. Were the groups similar at the start of the trial?
Yes. Overall, patients in the experimental and control groups had similar
baseline demographic and clinical characteristics, however more patients in the
amiodarone group had had a previous MI.
5. Aside from the experimental intervention, were the groups treated
Yes. All surgical and medical procedures were standardized using a predefined
critical pathway. The surgical intervention for each group was similar except
that patients in the amiodarone group had a slower heart rate during surgery
and required fewer intra-operative defibrillations to restore NSR after
cross-clamp release. The only co-intervention explicitly stated that was left
to the discretion of physicians was the antiarrhythmic treatment of post-op
6. Overall, are the results of the study valid?
What were the Results?
1. How large was the treatment effect?
The overall risk any AF in the 30-d post op period was 23% in the
amiodarone group and 38% in the placebo group (p=0.01), ARR = 15.5%
(3.4%-27.6%), NNT = 7 (4-30). Secondary analyses revealed the rate of
symptomatic AF was 4% in the amiodarone group and 18% in the placebo group
(p=0.001), ARR = 13.8% (5.5%-22.2%), NNT = 8 (5-19). Recurrent AF was 9% in
the amiodarone group and 20% in the placebo group (p=0.02), ARR = 10.9%
(1.5%-20.2%), NNT = 10 (5-69). The rate of ventricular tachycardia (>30
seconds) and cerebrovascular accidents (CVA) was 1.7% in the amiodarone group
and 7.0% in the placebo group (p=0.04), ARR = 5.3% (0.2%-10.8%), NNT = 19
There were no differences in withdrawal rates due to adverse effects in
either group, and there were no differences in bradycardia, heart block, need
for pacing, hypotension, or tolerability of upward titration of post-op BB
therapy. There was a trend towards more nausea in the amiodarone group (27%
vs. 16%, p=0.056). There were no differences in percentage of patients in
NSR at discharge, duration of ICU stay, hospital stay, in-hospital mortality,
30-day mortality, or treatment costs between the groups.
2. How precise was the estimate of the treatment effect?
For the primary outcome of any atrial fibrillation and secondary outcomes
of symptomatic AF and recurrent AF, the ARR did not cross zero, and the
confidence intervals around the point estimate were narrow and represent a
clinically significant result. For the analyses of ventricular tachycardia and
CVA, the confidence intervals also did not cross zero, however the intervals
were wide meaning the clinical significance can be questioned.
Will the Results Help Me in Caring for My Patients?
1. Can the results be applied to my patient care?
- Yes. Based on the AFIST trial, pre-operative oral amiodarone begun at
least 1 day pre-op and continued for 4 days post-op can reduce any AF,
symptomatic AF, and recurrent AF in patients >60 years old (mean 73
receiving pre-operative (mean = 89%)
the first trial comparing the effects of administering an antiarrhythmic
drug pre-operatively to eligible patients already receiving the gold
standard of pre-op/post-op BB prophylaxis.
These data should not be
extrapolated to younger patients not receiving pre/post-op
underlying event rate of atrial fibrillation in these groups would be
2. Were all clinically important outcomes considered?
Yes. Although this trial was underpowered to examine the effect of adding
amiodarone to the subgroup of patients who all received
, it did determine
the effect of adding amiodarone to a group of elderly post cardiac surgery
patients in whom pre-op/post-op
was attempted. Along with the
surrogate endpoint of development of post-op AF, other valuable morbidity,
mortality, and cost endpoints were evaluated in secondary analyses. Although
adverse drug reactions were prospectively evaluated and surveyed, the trial
was underpowered to detect rare, but clinically important adverse effects such
as acute lung injury and ARDS.
3. Are the likely treatment benefits worth the potential harms and costs?
- Yes. The benefits of reduction of any AF, symptomatic AF, and recurrent AF
are clinically important in this population, however a larger trial would be
required to clarify the ultimate impact of AF prevention on important
benefits such as incidence of CVA, length of stay, and economic outcomes.
Careful long-term follow up of post cardiac surgery patients
receiving amiodarone will still be
warranted to monitor for rare pulmonary toxicities.
AF is a common complication of cardiac surgery and is associated with a
significant impact on symptoms, morbidity, and health care costs.
and/or post-operative beta blocker
therapy is the gold standard for prevention of post
cardiac surgery AF, however, antiarrhythmic agents such as amiodarone and
sotalol have also been studied for prevention.
Conflicting results from studies
on the efficacy of amiodarone prophylaxis can be explained by differences in
study populations, prophylactic regimens, underutilization of proven beta
prophylaxis, and a falsely elevated AF rates due to post-op
blocker withdrawal in
The AFIST trial is the first trial specifically designed to
evaluate the effectiveness of prophylactic amiodarone added to gold standard BB
therapy in an elderly population, and reports significant reductions in post
cardiac surgery AF. These benefits are both statistically significant and
clinically important. Larger trials will be needed to clarify the impact of
this surrogate outcome on more important morbidity and economic outcomes such as
incidence of CVA and cost effectiveness of amiodarone prophylaxis. Judicious
monitoring of patients receiving any amiodarone prophylaxis regimen should
continue due to the potential for rare pulmonary toxicities.
Copyright © 2001 by the Journal of Informed
Pharmacotherapy. All rights reserved.