Circulation: Arrhythmia and Electrophysiology

RESEARCH LETTER

Pharmacological Cardioversion of Atrial

Tachyarrhythmias Using Single High-Dose Oral
Amiodarone: A Systematic Review and Meta-
Analysis
Lucy Y. Lei , BHSc; Derek S. Chew , MD, MSc; William Lee , MBBS, PhD; Ziran Meng, MD; Erkan Ilhan, MD;
Raffaello Furlan , MD; Robert S. Sheldon , MD, PhD; P. Timothy Pollak, MD, PhD*; Satish R. Raj , MD, MSCI*

A
trial tachyarrhythmias (ATAs) are common, with
≈25% lifetime prevalence >40 years.1 A recent
multicenter study of 2789 patients with ATA and
existing cardiovascular conditions found fewer major
adverse cardiovascular outcomes (hazard ratio=0.79
[0.66–0.94], P=0.005)2 with early rhythm control than
rate control. However, cardioversion to sinus rhythm
(SR) can be challenging. Electrical cardioversion is
highly effective but requires conscious sedation in
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continuity correction applied to studies with either zero
or all events. Subgroup analyses of pooled proportions
were performed to assess the impact of ATA duration
on cardioversion success. The conversion rate to SR
in patients receiving amiodarone versus placebo were
expressed as relative risks with 95% CIs. Heterogene-
ity was estimated with the I2 statistic. Analyses were
performed using R 3.5.1. All data and analytic software
are publicly available.

monitored hospital settings, and safety concerns limit
class IC medication use. A single, high dose of oral
amiodarone is appealing due to convenience, low cost,
and favorable safety profile. We performed a system-
atic review and meta-analysis to evaluate the efficacy
of single, high-dose oral amiodarone for pharma-
cological conversion of ATA within 24 hours of drug
administration.
We systematically searched the MEDLINE and
Embase databases without language restriction from
inception to August 2021. The search keywords were
related to “oral amiodarone,” “atrial tachyarrhythmia,”
and “cardioversion.” From 287 studies, we included 6
single-arm observational studies (n=149) and 3 clini-
cal trials (n=114), with 2 independent data extractions
from each study. The conversion success rates from
ATA to SR were expressed as proportions with 95%
CIs. Weighted pooled proportions were estimated using
random-effects generalized linear mixed models, with a
Across all 9 included studies, 263 patients received
oral amiodarone for acute conversion of ATA with minimal
adverse effects, including gastrointestinal disturbances
(nausea, vomiting, diarrhea, and digestive discomfort;
n=23); transient ataxia or tremor (n=2); or a rapid
ventricular response (n=4). Successful cardioversion
was achieved in 60% (27%–86%) of the 263 pooled
patients within 24 hours of amiodarone administration
(Figure). The high degree of heterogeneity among stud-
ies (I2=93%, P<0.01) was substantially reduced when
ATA was stratified by duration.
Four studies only included patients with acute ATA
within 48 hours of onset. SR was successfully restored
in 92% (81%–97%) of the 122 pooled participants
within 24 hours of amiodarone administration (I2=35%,
P=0.29). When assessing only the 2 placebo-controlled
randomized controlled trials, 86% (76%–92%) of par-
ticipants receiving amiodarone were restored to SR ver-
sus 25% (15%–40%) of those receiving placebo. Oral

Key Words: amiodarone ◼ atrial fibrillation ◼ meta-analysis ◼ systematic review

 
Correspondence to: Satish R. Raj, MD, MSCI, Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, GAC70 HRIC Bldg, 3280 Hospital
Drive NW, Calgary, AB T2N 4Z6, Canada. Email satish.raj@ucalgary.ca
*P.T. Pollak and S.R. Raj are joint senior authors.
For Sources of Funding and Disclosures, see page 1102.
© 2021 American Heart Association, Inc.
Circulation: Arrhythmia and Electrophysiology is available at www.ahajournals.org/journal/circep

Circ Arrhythm Electrophysiol. 2021;14:e010321. DOI: 10.1161/CIRCEP.121.010321 December 2021 1099

 Lei et al
Nonstandard Abbreviations and Acronyms
ATA atrial tachyarrhythmia
SR sinus rhythm
amiodarone significantly increased the rate of conver-
sion compared with placebo (relative risk=3.32 [1.67–
6.61], P<0.01). An additional 4 studies included a total
of 112 participants with recent-onset ATA within 14 days
of onset. In this subgroup, 53% (42%–64%) of partici-
pants were converted to SR within 24 hours of treat-
ment (I2=24%, P=0.17). Finally, 3 observational cohorts
including 29 patients with long-standing persistent ATA
lasting at least 1 year found only 5% (0%–46%) cardio-
version success with oral amiodarone (I2=45%, P=1.00).
Although electrical cardioversion is an effective ther-
apy for achieving SR in patients with symptomatic ATA,
chemical cardioversion is less resource intensive and
carries lower associated procedural risks. In contrast
to class IC medications, oral amiodarone is indicated
for use in patients with ischemic and structural heart
disease, significantly expanding its use case. Active-
controlled randomized controlled trials of oral cardiover-
sion medications have found similar 24-hour conversion
rates between amiodarone versus flecainide (relative
risk=1.20 [0.40–3.62], P=0.8) and propafenone (relative
risk=1.05 [0.91–1.21], P=0.5).3,4
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Given the large volume of distribution and long
elimination half-life of amiodarone, a minimum dose of
2000 mg is likely necessary to produce an acute rise in
serum concentration to the therapeutic levels required
to promptly control ATA.5 Since the drug has long been
available in generic form, a 200 mg tablet of amiodarone
hydrochloride costs $0.30 USD, giving a 2000 mg total
dose cost of $3.00 USD, making it a potential low-cost
treatment strategy.
To date, there remains limited high-quality data
supporting the use of oral amiodarone for conver-
sion of ATA. The number of patients studied is small,
and prior randomized controlled trials were conducted
in heterogenous populations, only included patients
with acute ATA, and lacked long-term community fol-
low-up. While this meta-analysis demonstrates that
a single, high oral dose of amiodarone was largely
Circ Arrhythm Electrophysiol. 2021;14:e010321. DOI: 10.1161/CIRCEP.121.010321
Oral Amiodarone for Conversion of Tachyarrhythmias
effective in converting patients with recent-onset ATA
to SR, these findings were based on pooled data and
not individual patient data and should be confirmed
in a formal randomized controlled trial to evaluate the
clinical efficacy of oral amiodarone as a safe and con-
venient therapy.
ARTICLE INFORMATION
Affiliations
Department of Cardiac Sciences, Libin Cardiovascular Institute, University of
Calgary, AB, Canada (L.Y.L., D.S.C., W.L., E.I., R.S.S., P.T.P., S.R.R.). Duke Clinical
Research Institute, Duke University, Durham, NC (D.S.C.). Department of Medi-
cine, Queen Elizabeth II Health Sciences Center, Dalhousie University, Halifax,
NS, Canada (Z.M.). Department of Medicine, Humanitas Clinical and Research
Center, IRCCS, Humanitas University, Rozzano, Italy (R.F.). Division of Clinical
Pharmacology, Department of Medicine, Vanderbilt University Medical Center,
Nashville, TN (S.R.R).
Sources of Funding
The support was received from the Vanderbilt Institute for Clinical and Trans-
lational Research (VICTR), which is funded by the National Institutes of Health
grant 5UL1TR002243 (Bethesda, MD).
Disclosures
Dr Raj is a consultant to Lundbeck LLC and Theravance Biopharma related to
neurogenic orthostatic hypotension; receives honoraria from Academy for Con-
tinued Healthcare Learning for developing CME slides kits on neurogenic ortho-
static hypotension; is the DMSB Chair for a Phase 2 study of an irritable bowel
syndrome medication for Arena Pharmaceuticals with compensation, and a past-
president of the American Autonomic Society without financial compensation. No
disclosures related to atrial fibrillation or amiodarone. The others authors report
no conflicts.
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 Lei et al Oral Amiodarone for Conversion of Tachyarrhythmias

Figure. Random-effects model analysis of successful cardioversion with amiodarone.

A, The proportion of patients with successful conversion from atrial tachyarrhythmia to sinus rhythm within 24 hours of oral amiodarone
administration, stratified by arrhythmia duration, and (B) the relative risk (RR) of successful cardioversion in patients administered oral
amiodarone vs matching placebo.
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