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Annals of Internal Medicine
Amiodarone Prophylaxis Reduces Major Cardiovascular Morbidity and
Length of Stay after Cardiac Surgery: A Meta-Analysis
Johan D. Aasbo, DO; Andrew T. Lawrence, MD; Kousik Krishnan, MD; Michael H. Kim, MD; and Richard G. Trohman, MD
Background:
Although evidence supports the prophylactic use
of ␤-blockade in cardiac surgery, postoperative atrial fibrillation or
flutter occurs in 40% to 60% of patients. Trials that assessed
whether amiodarone prophylaxis decreases the incidence of postoperative atrial tachyarrhythmias have had mixed results and were
not specifically powered to detect changes in cardiovascular morbidity, length of stay, or mortality.
Purpose: To see whether prophylactic administration of amiodarone decreases the incidence of major cardiovascular events,
length of stay, and mortality after cardiac surgery.
Data Sources: English-language and non–English-language publications listed in the MEDLINE, EMBASE, and CINAHL databases
and the Cochrane Central Register of Controlled Trials, and bibliographies of published reviews. Sources were searched from the
earliest possible dates through February 2005.
Study Selection:
Double-blind, randomized studies comparing
amiodarone with placebo that reported the incidence of supraventricular arrhythmia, atrial fibrillation, or atrial flutter as the primary
end point.
Data Extraction: Two investigators independently collected all
data. Discrepancies were resolved by consensus.
patients, amiodarone therapy was found to decrease the incidence
of atrial fibrillation or flutter (relative risk, 0.64 [95% CI, 0.55 to
0.75]), ventricular tachycardia and fibrillation (relative risk, 0.42
[CI, 0.28 to 0.63]), stroke (relative risk, 0.39 [CI, 0.21 to 0.76]),
and length of stay (weighted mean difference, ⴚ0.63 day [CI,
ⴚ1.03 to ⴚ0.23 days]). All studies reported adverse events, but
none indicated how these events were assessed. Three studies
found significantly more adverse events with amiodarone therapy,
including nausea permitting continuation of therapy, bradycardia
of unclear clinical significance, and increased intensive care monitoring and support.
Limitations: Not all studies used ␤-blockade, and regimens
were not uniform among trials. Few trials met the stringent inclusion criteria, some did not report each type of cardiovascular
event, and none reported completeness of follow-up.
Conclusions: Amiodarone prophylaxis decreases the occurrence
of atrial fibrillation, ventricular tachyarrhythmias, and stroke and
length of stay after cardiac surgery. To further evaluate the potential benefits of concomitant prophylaxis with ␤-blockers and
amiodarone, a multicenter, randomized, double-blind trial with
cardiovascular outcomes that compares amiodarone with placebo
in patients already receiving ␤-blocker prophylaxis is needed.
Data Synthesis:
After DerSimonian–Laird random-effects models were used to combine data from 10 trials involving 1744
Ann Intern Med. 2005;143:327-336.
For author affiliations, see end of text.
A
noncompetitive ␤-receptor antagonism. Sinus bradycardia
develops more gradually as a function of time while receiving a constant dose (11). Short-term amiodarone administration also blocks sodium channels (making the threshold
voltage for activation more positive), thereby reducing automaticity (ectopic triggers) and prolonging conduction
velocity (length of the tachycardia cycle) (12–14). Amiodarone may also reduce automaticity by decreasing the recruitment of voltage-dependent inward current (the “pacemaker current”) during spontaneous depolarization,
reducing the slope of phase 4 of the action potential (14).
Long-term therapy (weeks to months) results in prolongation of atrial and ventricular effective refractory periods
because of potassium blockade (11, 15).
trial fibrillation and atrial flutter are common after
cardiac surgery. Studies have estimated their incidence
to be as high as 40% to 60% after coronary artery bypass
grafting or cardiac valve surgery (1, 2). These arrhythmias
most often develop between the second and fifth postoperative day (3), with a peak incidence in the first 2 to 3
days (4). Atrial fibrillation and atrial flutter increase the
occurrence of postoperative stroke (4), perioperative myocardial infarction, heart failure, and readmission to the intensive care unit (and reintubation) (5); length of stay; and
total cost of hospitalization (6, 7). Recent data suggest that
atrial fibrillation and atrial flutter are independent risk factors for inpatient and long-term mortality after open-heart
surgery (8).
Amiodarone has complex pharmacokinetics and pharmacodynamics. Although it is categorized as a Vaughn–
Williams class III agent, amiodarone combines anti–␤-adrenergic effects (9) with sodium-, calcium-, and potassiumchannel blocking properties (10). Striking pharmacologic
and therapeutic differences between short-term and longterm administration are not readily accounted for by
plasma, tissue, or membrane levels of drug. The most rapid
electrophysiologic effects of amiodarone are prolongation
of AV nodal refractoriness and conduction time. These
effects probably result from calcium-channel blockade and
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Editors’ Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-26
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Appendix Tables
Conversion of figures and tables into slides
© 2005 American College of Physicians 327
Article
Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery
Context
Tachyarrhythmias are common after heart surgery and are
associated with increased morbidity.
Contribution
This meta-analysis of 10 randomized, double-blind trials
involving 1744 patients undergoing open-heart surgery
found that, compared with placebo, amiodarone reduced
atrial and ventricular arrhythmias, stroke, and length of
hospital stay. Side effects included nausea and bradycardia
that was not always deemed clinically important.
Cautions
Trial participants did not always receive prophylaxis with
␤-blockers. Dosages and timing of amiodarone and length
of follow-up varied across studies.
Implications
Amiodarone may benefit some patients undergoing heart
surgery. We now need trials of prophylaxis with both
␤-blockers and amiodarone.
–The Editors
Clinical trials of varying size and design have evaluated
the efficacy of amiodarone in reducing the incidence of
atrial fibrillation and atrial flutter after cardiac surgery
(16 –22). No prospective studies have intentionally been
powered to detect decreases in major cardiovascular morbidity or mortality. Current American College of Cardiology/American Heart Association/European Society of Cardiology guidelines recommend ␤-blocker therapy for all
patients (without contraindications) before cardiac surgery
and reserve therapy with amiodarone for patients at increased risk for postoperative atrial fibrillation and atrial
flutter (those with a history of atrial fibrillation, left atrial
enlargement, or valvular heart disease) (23).
We performed a meta-analysis to compare the effect of
treatment with amiodarone or placebo on the incidence of
atrial fibrillation and atrial flutter, the incidence of major
cardiovascular morbidity (ventricular tachycardia or fibrillation, stroke, or myocardial infarction), length of stay, and
death. Subgroup analyses were done to compare patients
who began amiodarone prophylaxis up to 13 days before
surgery with those who received amiodarone intraoperatively or immediately postoperatively, and patients who received oral amiodarone with those who received intravenous amiodarone.
METHODS
Literature Search
We conducted this review in accordance with recommendations put forth by the QUOROM Group (24). We
searched the English-language and non–English-language
literature by using MEDLINE, EMBASE, and CINAHL
328 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5
databases and the Cochrane Central Register of Controlled
Trials from the earliest searchable dates through February
2005. Search terms were atrial fibrillation, amiodarone, and
surgery. We also searched the bibliographies of published
reviews but excluded unpublished data.
Data Collection
Inclusion criteria for the meta-analysis were established before the literature search. Studies had a randomized, controlled, double-blind design to compare amiodarone with placebo; included patients who underwent
coronary artery bypass grafting or cardiac valve surgery (or
both); measured the occurrence of atrial fibrillation, atrial
flutter, or supraventricular tachycardia as a primary outcome; and clearly described drug administration, comorbid
conditions, the risk profile of study cohorts, study design,
and methods.
One author screened titles and abstracts before manuscript retrieval. Three authors read all retrieved manuscripts and made the final decision on which studies met
the inclusion criteria. All data were abstracted independently and in duplicate by 2 of the authors by using a
standardized data collection form. Discrepancies in the
data abstracted were resolved by consensus among all authors. We assessed reported randomization methods and
completeness of follow-up but avoided use of a formal or
aggregated score for quality assessment because such use
can produce inconsistent results (25).
Statistical Analysis
Incidences of atrial fibrillation, atrial flutter, stroke,
ventricular tachycardia or fibrillation, myocardial infarction, and death were treated as dichotomous variables.
Summary effects for the dichotomous variables were calculated as relative risks. Length of stay was treated as a continuous variable. The summary effect for data on length of
stay was calculated as the weighted mean difference. Data
on length of stay were included in calculating the summary
effect only if both the mean and standard deviation were
specified.
We pooled data by using the DerSimonian–Laird random-effects model (26). Statistical heterogeneity for all
variables was assessed by using the I2 measure because this
measure is independent of the number of studies that are
pooled and of the effect-size metric (27). To assess for
possible publication bias, we used the test proposed by
Egger and colleagues (28), which provides an assessment of
funnel-plot asymmetry (expressed as a P value) by applying
an inverse-variance weighted approach. For each variable,
studies were assigned a Mantel–Haenszel weight that was
directly proportional to the sample size and inversely proportional to the variance of each study.
For subgroup analysis, studies were organized into 2
categories according to when amiodarone or placebo was
initially administered. Studies were categorized as “preoperative” if administration of amiodarone or placebo began
before surgery or “perioperative” if drug or placebo was
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Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery
administered during or immediately after surgery. To compare the efficacy of oral versus intravenous administration
of amiodarone, we excluded trials in which both routes
were used.
Publication bias was assessed by using StatsDirect software, version 2.3.1 (StatsDirect Ltd., Sale, United Kingdom). All other statistical calculations were performed by
using Review Manager (RevMan) statistical software, version 4.2.7 for Windows (The Cochrane Collaboration,
Oxford, United Kingdom). Continuous data are expressed
as the mean and standard deviation, unless otherwise specified. A 2-sided P value less than 0.05 was considered significant.
Article
Figure 1. Flow diagram of study selection.
Role of the Funding Source
We received no intramural or extramural funding for
this study.
RESULTS
Figure 1 shows the trial selection process. Searches
identified 1989 potentially relevant citations. Of these, we
considered and retrieved 17 citations for possible inclusion
in the meta-analysis (16 –22, 29 –38). We excluded 4 studies because they were not double-blind (16 –18, 22), 1
because it compared amiodarone with propranolol rather
than placebo (19), 1 because the characteristics of the participants and details of the study methods were not provided (20), and 1 because the amiodarone regimen (a single oral dose of 1.2 g) differed markedly from those used in
other studies (21).
Table 1 provides information on the patients and design of the included studies. One thousand seven hundred
forty-four patients were included. In 4 studies, amiodarone
or placebo was administered before surgery. In 6 studies,
therapy was given during or immediately after surgery. Five
studies included patients who underwent coronary artery
bypass grafting only, and 5 included patients who had coronary artery bypass grafting or valve surgery. All patients
received at least 2 g of amiodarone by the second postoperative day. Amiodarone was administered orally in 5 studies, intravenously in 2 studies, and both orally and intravenously in 3 studies. Eight studies reported ventricular
tachycardia and fibrillation, 8 reported stroke, and 4 reported myocardial infarction. Follow-up data were limited
to inpatient stay for all studies except that by Giri and
associates (34), which included information on death at 30
days. No study included in our analysis gave data on adequacy of patient follow-up (dropout rate).
Table 2 shows medical and surgical data for the included patients. The mean patient age was 64.4 years, and
the mean left ventricular ejection fraction was 0.492. At
the time of surgery, a mean of 61.1% of patients were
receiving a ␤-blocker. Four studies excluded patients with a
history of supraventricular tachycardia. In the studies that
included such patients, only 6.5% in total had supraventricular tachycardia. Eight of ten studies excluded patients
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VF ⫽ ventricular fibrillation; VT ⫽ ventricular tachycardia.
who were taking any Vaughn–Williams class I or III antiarrhythmic drug. Of the studies including patients taking
antiarrhythmic drugs, 1 study (35) excluded patients with
a history of supraventricular tachycardia, and the other
(30) excluded patients taking amiodarone. Appendix Table 1 and Appendix Table 2 (available at www.annals.org)
describe the cohorts of each study in greater detail.
Compared with placebo, amiodarone decreased the incidence of atrial fibrillation and atrial flutter (relative risk,
0.64 [95% CI, 0.55 to 0.75]; P ⬍ 0.001) (Figure 2). The
decrease in the incidence of atrial fibrillation and atrial
flutter was similar regardless of whether amiodarone therapy was initiated preoperatively or perioperatively (relative
risk, 0.62 [CI, 0.49 to 0.78] and 0.65 [CI, 0.53 to 0.81],
respectively). Oral administration of amiodarone yielded
similar results to intravenous administration (relative risk,
0.62 [CI, 0.49 to 0.78] and 0.67 [CI, 0.51 to 0.88], respectively).
Amiodarone therapy decreased the incidence of ventricular tachycardia and fibrillation (relative risk, 0.42 [CI,
0.28 to 0.63]; P ⬍ 0.001) (Figure 3). Elimination of the
studies that did not differentiate between sustained and
nonsustained ventricular tachycardia or fibrillation (30, 33)
did not markedly change the results (relative risk, 0.34 [CI,
0.18 to 0.66]). Amiodarone therapy also decreased the incidence of stroke (relative risk, 0.39 [CI, 0.21 to 0.76];
6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 329
Article
Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery
Table 1. Randomized, Controlled Trials Included in the Meta-Analysis*
Study, Year
(Reference)
Patients,
n
Type of Surgery
Timing of
Amiodarone or
Placebo
Administration
Total
Amiodarone
Dose, g
Dose and Route of Amiodarone
Administration
Primary
Arrhythmia
Butler et al., 1993
(30)
120
CABG
Perioperative
4.5
Any SVT
Daoud et al., 1997
(32)
124
CABG or valve,
or both
Preoperative
Indeterminate
Intravenous, 15 mg/kg of body weight
(maximum of 1.5 g) over 24 h,
initiated intraoperatively; then oral,
200 mg TID for 5 d
Oral, 200 mg TID for 7 d, then 200
mg daily until discharge; dose
halved if patient was receiving
digoxin or warfarin concomitantly†
Redle et al., 1999
(33)
143
CABG
Preoperative
6.2
Oral, 2-g load over 5 d before surgery;
then 400 g daily after surgery for
7d
AF or AFL
Guarnieri et al., 1999
(31)
300
CABG or valve,
or both‡
Perioperative
2.0
Intravenous, 2-g load over 48 h,
started within 3 h of ICU arrival
AF or AFL
Treggiari-Venzi, et al.,
2000 (35)
100
CABG
Perioperative
2.7
Intravenous, 2.7 g over 72 h, started
within 1 h of ICU arrival
AF or AFL
Giri et al., 2001 (34)
220
CABG or valve,
or both
Preoperative
Method 1,
7.5
Method 2,
6.0
AF or AFL
White et al., 2002
(29)
220
CABG or valve,
or both
Preoperative
Method 1:
7.5
Method 2:
6.0
Yazigi et al., 2002
(36)
200
CABG
Perioperative
4.65
Method 1: Oral, 200 mg TID for 5 d
before surgery, then 400 mg BID on
day of surgery and on postoperative
days 1–4; method 2: Oral, 400 mg
QID for 1 d, then 600 mg BID on
day of surgery, then 400 mg BID on
postoperative days 1–4
Method 1: 400 mg QID for 1 d, then
600 mg BID on day of surgery, then
400 mg BID on postoperative days
1–4; method 2: 200 mg TID for 5 d
before surgery, then 400 mg BID on
day of surgery and postoperative
days 1–4
Oral, load of 15 mg/kg of body
weight, then 7 mg/kg daily until
discharge; therapy initiated within 4
h of ICU arrival
Yagdi et al., 2003
(38)
157
CABG
Perioperative
Indeterminate
AF
White et al., 2003
(37)
160
CABG or valve,
or both
Perioperative
6.9 (oral
equivalents)
Intravenous, 10 mg/kg of body weight
daily for 48 h; then oral, 600 mg
TID for 5 d; then 400 mg BID for 5
d; then 200 mg for 20 d; initiated
within 2 h of ICU arrival
Intravenous, 1050-mg load over 24 h,
then oral, 400 mg TID on
postoperative days 1–4
AF or AFL
AF or AFL
AF or AFL
AF or AFL
* AF ⫽ atrial fibrillation; AFL ⫽ atrial flutter; BID ⫽ twice daily; CABG ⫽ coronary artery bypass grafting; CT ⫽ computed tomography; CVA ⫽ cerebrovascular accident;
ICU ⫽ intensive care unit; MRI ⫽ magnetic resonance imaging; NA ⫽ not applicable; NS ⫽ not specified; QID ⫽ 4 times daily; SVT ⫽ supraventricular tachycardia; TIA ⫽
transient ischemic attack; TID ⫽ 3 times daily.
† Average presurgical stay was 13 days (SD, 7).
‡ One patient had atrial septal defect repair at the time of bypass surgery.
P ⫽ 0.005) (Figure 4) and length of stay (weighted mean
difference, ⫺0.63 day [CI, ⫺1.03 to ⫺0.23 days]; P ⫽
0.002) (Figure 5). No statistically significant differences in
mortality between the amiodarone and placebo cohorts
were seen (relative risk, 0.84 [CI, 0.43 to 1.65]). For these
estimates, we found no evidence of statistical heterogeneity
or publication bias (P ⫽ 0.169, 0.133, 0.317, 0.230, and
0.959 for the incidence of atrial arrhythmias, ventricular
330 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5
arrhythmias, stroke, length of stay, and mortality, respectively).
The incidence of myocardial infarction did not significantly differ between groups (relative risk, 0.71 [CI, 0.31 to
1.62]). Twenty-two myocardial infarctions were reported in
the 4 trials that documented their occurrence. We found no
statistical heterogeneity for this outcome and could not assess
publication bias because there were too few studies.
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Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery
Article
Table 1—Continued
Method and
Duration of Patient
Monitoring
Randomization
Methods and
Blinding
Funding
Sources
Intention-toTreat
Analysis?
Definition of
Ventricular
Tachycardia
Definition of Stroke
Description
of
Myocardial
Infarction
Mortality
Assessment
Holter monitor, 6 d
postoperatively
NS
Pharmaceutical
support
Yes
NS
New Q
waves
Inpatient
Telemetry, 7.2 d
(SD, 3.6)
NS
Pharmaceutical
support
Yes
Sustained (⬎30 s)
or nonsustained (⬎3
beats)
NS
NS
Inpatient
Telemetry, not less
than 96 h
postoperatively
Stratified/
factorial
NS
Yes
NS
Continuous
ambulatory
monitor,
duration not
specified
Holter monitor,
during 72 h of
amiodarone
infusion
Telemetry, duration
not specified
NS
Pharmaceutical
support
Yes
Sustained (⬎30 s)
or nonsustained (⬎3
beats)
NS
Right
ventricular
infarction
and
sepsis
NA
NS
NA
Inpatient
Stratified/
factorial
Pharmaceutical
support
No
NA
NS
NA
Inpatient
Stratified/
factorial
NS
Yes
Sustained (⬎30 s)
or requiring
termination
TIA (focal defect
⬍24 h) or CVA
(lasting ⬎24 h,
with CT or MRI
confirmation)
NA
30 d
Telemetry, duration
not specified
Stratified/
factorial
Financial
support
from
hospital
research
foundation
Yes
Sustained (⬎30 s)
or requiring
termination
TIA (focal defect
⬍24 h) or CVA
(lasting ⬎24 h,
with CT or MRI
confirmation)
NA
Inpatient
Telemetry for 72 h,
then vital checks
every 4 h and
electrocardiography
every 12 h
Telemetry until
discharge
NS
NS
Yes
NS
NA
NA
Inpatient
NS
NS
NS
NS
NS
NS
Inpatient
Stratified/
factorial
Pharmaceutical
support
NS
NA
TIA (focal defect
⬍24 h) or CVA
(lasting ⬎24 h,
with CT or MRI
confirmation)
NS
Inpatient
Telemetry, duration
not specified
All 10 studies reported adverse events, but none indicated whether these events were reported incidentally or
determined as end points a priori. Three studies reported
significantly higher rates of adverse events that may have
been related to amiodarone therapy. Butler and coworkers
(30) noted a significantly higher incidence of bradycardia
among amiodarone recipients (P ⫽ 0.005). The clinical
significance of these bradycardia episodes was not eluciwww.annals.org
Inpatient
dated. Treggiari-Venzi and associates (35) reported a significantly increased duration of catecholamine support
(P ⬍ 0.01), use of pulmonary artery catheters (P ⬍ 0.01),
and stay in the intensive care unit (P ⬍ 0.05) among amiodarone recipients. White and colleagues (29) found a significantly increased incidence of nausea (not requiring termination of therapy) with a higher-dose, shorter-duration
amiodarone loading regimen (P ⫽ 0.018).
6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 331
Article
Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery
Table 2. Medical and Surgical Characteristics of Patient Cohorts*
Study, Year (Reference)
Patients,
n
Mean
Age, y
Men,
%
History of
Supraventricular
Tachycardia, %
History of
Myocardial
Infarction,
%
History of
Hypertension,
%
Butler et al., 1993 (30)
Daoud et al., 1997 (32)
Redle et al., 1999 (33)
Guarnieri et al., 1999 (31)
Treggiari-Venzi et al., 2000 (35)
Giri et al., 2001 (34)
White et al., 2002 (29)
Yazigi et al., 2002 (36)
Yagdi et al., 2003 (38)
White et al., 2003 (37)
Mean (SD)
120
124
143
300
100
220
220
200
157
160
59.5
59
63.8
63.6
65
72.6
72.6
60.6
61.1
65.9
64.4 (4.9)
85.3
67.8
82.5
75.5
86.1
76.2
76.4
65.0
77.1
75.8
76.8 (6.8)
NS
7.3
None in past 6 mo
None†
3.0
9.7
10
None†
None†
2.5
6.5 (3.6)
53.4
30.7
NS
40.2
45.3
34.6
35.5
16.0
46.5
25.6
36.4 (11.5)
38.4
50.0
53.3
73.2
41.2
70.7
70.5
39.0
57.8
NS
54.9 (14.0)
* Appendix Tables 1 and 2 (available at www.annals.org) describe the cohorts in greater detail. NS ⫽ not specified.
† Supraventricular tachycardia was an exclusion criterion.
DISCUSSION
incidence of atrial fibrillation and atrial flutter (16, 18, 22),
and 1 reported that it decreased the incidence of ventricular arrhythmias (18). Two studies reported no significant
difference in length of stay between amiodarone recipients
and placebo recipients (16, 22), 3 studies reported no significant difference in mortality (16 –18), and 1 study (22)
did not report on mortality. No study found a significant
reduction in the incidence of stroke, and no occurrence of
myocardial infarction was reported.
No study included in our analysis provided a subgroup
analysis of patients with low ejection fraction. However,
Butler and coworkers (30) and Redle and associates (33)
found that depressed ejection fraction did not predict atrial
fibrillation and atrial flutter. Giri and colleagues (34)
found left atrial enlargement and clinical history of heart
The pivotal finding of our meta-analysis is that treatment with amiodarone decreases the incidence of major
postoperative cardiovascular events (ventricular tachycardia, ventricular fibrillation, and stroke). Previous metaanalyses suggest that amiodarone therapy decreases the
incidence of atrial fibrillation and atrial flutter after openheart surgery (39 – 41). Our analysis confirms that amiodarone prophylaxis decreases rates of these tachyarrhythmias
and shortens the length of hospitalization.
Whereas previous meta-analyses included unblinded
studies, we excluded such trials in an attempt to minimize
bias. In the 4 unblinded studies that we excluded (16 –18,
22) the results of amiodarone prophylaxis varied. Three
studies reported that amiodarone prophylaxis decreased the
Figure 2. Incidence of atrial fibrillation or flutter with amiodarone or placebo.
Random RR
Weight,
%
Random RR
(95% CI)
Study, Year (Reference)
Amiodarone Group,
n/n
Placebo Group,
n/n
Butler et al., 1993 (30)
12/60
12/60
4.43
1.00 (0.49–2.05)
Daoud et al., 1997 (32)
15/64
25/60
7.95
0.56 (0.33–0.96)
Redle et al., 1999 (33)
18/73
23/70
8.32
0.75 (0.45–1.27)
Guarnieri et al., 1999 (31)
56/158
67/142
30.46
0.75 (0.57–0.99)
7/49
14/51
3.39
0.52 (0.23–1.18)
Giri et al., 2001 (34)
28/120
38/100
13.53
0.61 (0.41–0.92)
White et al., 2002 (29)
27/120
38/100
13.13
0.59 (0.39–0.90)
Yazigi et al., 2002 (36)
12/100
25/100
5.72
0.48 (0.26–0.90)
Yagdi et al., 2003 (38)
8/77
20/80
3.95
0.42 (0.19–0.89)
White et al. (AFIST II), 2003 (37)
17/77
32/83
9.09
0.57 (0.35–0.94)
100.00
0.64 (0.55–0.75)
Treggiari-Venzi et al., 2000 (35)
Total
898
846
0.1
0.2
0.5
Favors Amiodarone
1
2
5
10
Favors Placebo
AFIST ⫽ Atrial Fibrillation Suppression Trial; RR ⫽ relative risk.
332 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5
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Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery
Article
Table 2—Continued
History of
Diabetes
Mellitus,
%
Left
Ventricular
Ejection
Fraction
Use of
␤-Blocker,
%
Duration of
Cardiopulmonaary
Bypass, min
Patients Who
Received
Valve
Surgery, %
Duration of
Cross-Clamping,
min
Mean
Vessels
Grafted,
n
7.5
14.5
25.9
30.0
19.2
32.6
NS
26.0
28.7
NS
23.1 (8.6)
0.63
0.48
0.485
0.445
0.575
0.427
0.427
NS
0.475
0.482
0.492 (0.068)
79.2
35.3
58.8
51.6
59.9
72.4
89.1
66.5
25.6
72.4
61.1 (19.5)
55.8
151.0
77.0
97.8
152.5
119.3
119.1
99.0
67.4
NS
104.3 (34.4)
None
50.9
None
14.7
None
26.9
18.2
None
None
21.2
26.4 (14.4)
34.0
100.5
NS
NS
101.5
88.8
88.7
50.0
42.5
96.2
75.3 (28.1)
2.7
2.6
3.3
4.1
3.0
2.4
NS
2.8
3.0
3.4
3.0 (0.5)
failure symptoms to be predictive of atrial fibrillation and
atrial flutter (P ⬍ 0.001 and 0.032, respectively). Daoud
and coworkers (32) found that valve surgery independently
predicted atrial fibrillation and atrial flutter (P ⫽ 0.04).
Adverse events possibly related to amiodarone therapy
occurred significantly more often in the amiodarone
groups of 3 studies (29, 30, 35). These events warrant
consideration, but the data are not conclusive. One study
reported an increased occurrence of clinically unimportant
nausea (29). In the studies that reported a higher incidence
of bradycardia and increased duration of catecholamine
support, use of pulmonary artery catheters, and intensive
care unit stay (30, 35), the blinding code was broken when
the primary end point of arrhythmia occurred, possibly
before the occurrence of the adverse event. This decision
raises the question of whether bias occurred. None of the
trials were specifically designed to assess adverse events due
to amiodarone therapy.
Of note, patients who underwent amiodarone loading
during or immediately after surgery had similar reductions
in the incidence of atrial fibrillation and atrial flutter
compared with those who underwent loading days before
surgery. This finding suggests that prescribing oral amiodarone days before surgery is unnecessary. Prolonged amiodarone prophylaxis may increase length of hospitalization,
costs, and patient inconvenience. On the other hand, perioperative intake and absorption of oral amiodarone may be
limited. Administration of the more expensive intravenous
preparation may counterbalance any cost benefit of abbreviated regimens.
Two meta-analyses found no difference in the incidence of stroke in patients who received amiodarone ther-
Figure 3. Incidence of ventricular tachycardia or fibrillation with amiodarone or placebo.
Weight,
%
Random RR
(95% CI)
38.17
0.45 (0.24–0.88)
2/60
1.81
0.19 (0.01–3.83)
13/70
22.31
0.52 (0.22–1.22)
2/142
1.79
0.18 (0.01–3.72)
2/120
7/100
6.85
0.24 (0.05–1.12)
White et al., 2002 (29)
2/120
7/100
6.85
0.24 (0.05–1.12)
Yazigi et al., 2002 (36)
1/100
0/100
1.62
3.00 (0.12–72.77)
Yagdi et al., 2003 (38)
6/77
20.59
0.42 (0.17–1.02)
100.00
0.42 (0.28–0.63)
Study, Year (Reference)
Amiodarone Group,
n/n
Placebo Group,
n/n
Butler et al., 1993 (30)
10/60
22/60
Daoud et al., 1997 (32)
0/64
Redle et al., 1999 (33)
7/73
Guarnieri et al., 1999 (31)
0/158
Giri et al., 2001 (34)
Total
772
Random RR
15/80
712
0.1
0.2
0.5
Favors Amiodarone
1
2
5
10
Favors Placebo
RR ⫽ relative risk.
www.annals.org
6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 333
Article
Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery
Figure 4. Incidence of stroke with amiodarone or placebo.
Study, Year (Reference)
Amiodarone Group,
n/n
Placebo Group,
n/n
Butler et al., 1993 (30)
1/60
0/60
Daoud et al., 1997 (32)
1/64
Guarnieri et al., 1999 (31)
2/158
Giri et al., 2001 (34)
4/120
White et al., 2002 (29)
Random RR
Weight,
%
Random RR
(95% CI)
4.24
3.00 (0.12–72.20)
0/60
4.24
2.82 (0.12–67.80)
3/142
13.62
0.60 (0.10–3.53)
12/100
35.45
0.28 (0.09–0.83)
2/120
7/100
17.88
0.24 (0.05–1.12)
Yazigi et al., 2002 (36)
0/100
1/100
4.22
0.33 (0.01–8.09)
Yagdi et al., 2003 (38)
2/77
4/80
15.41
0.52 (0.10–2.75)
White et al. (AFIST II), 2003 (37)
0/77
3/83
4.94
0.15 (0.01–2.93)
100.00
0.39 (0.21–0.76)
776
Total
725
0.1
0.2
0.5
1
2
Favors Amiodarone
5
10
Favors Placebo
AFIST ⫽ Atrial Fibrillation Suppression Trial; RR ⫽ relative risk.
apy (40, 41). Our apparent discrepant results may be due
to the fact that we included recent studies (29, 36 –38) that
were not included in the earlier reviews. The annual incidence of stroke associated with atrial fibrillation and atrial
flutter in nonsurgical patients is approximately 5%. On the
basis of this value, it seems unlikely that decreasing the
incidence of postoperative atrial fibrillation and atrial flutter would cause a measurable decrease in the incidence of
stroke solely by diminishing embolization of atrial
thrombi. Indeed, the incidence of embolization due to
atrial fibrillation and atrial flutter may be lower in postsurgical patients than in nonsurgical patients (42). The reduc-
tion in stroke observed may also be attributable to prevention of low cardiac output states, increased sympathetic
tone, and other factors associated with postoperative atrial
fibrillation and atrial flutter.
Amiodarone was synthesized in 1962 as a potent antianginal agent (43). Its antiarrhythmic effects were first
noted in 1967 (44), but it was not approved by the U.S.
Food and Drug Administration as an antiarrhythmic agent
until 1985 (45). Although amiodarone therapy reduced the
relative risk for myocardial infarction in our analysis, this
finding was not statistically significant. Unfortunately, only
4 trials reported 22 myocardial infarctions. The decrease
Figure 5. Length of hospitalization with amiodarone or placebo.
Patients,
n
Mean Stay (SD), d
Random Weighted
Mean Difference
Placebo Group
Amiodarone Group
Study, Year (Reference)
Patients, Mean Stay (SD), d
n
Weight,
%
Random Weighted Mean
Difference (95% CI)
64
6.50 (2.60)
60
7.90 (4.30)
9.43
–1.40 (–2.66 to –0.14)
Guarnieri et al., 1999 (31)
158
7.60 (5.90)
142
8.20 (6.20)
8.02
–0.60 (–1.97 to 0.77)
Giri et al., 2001 (34)
120
9.16 (8.20)
100
9.35 (7.80)
3.47
–0.19 (–2.31 to 1.93)
White et al., 2002 (29)
120
9.10 (7.80)
100
9.40 (7.80)
3.63
–0.30 (–2.37 to 1.77)
Yazigi et al., 2002 (36)
100
6.80 (1.30)
100
7.10 (2.00)
49.84
–0.30 (–0.77 to 0.17)
Yagdi et al., 2003 (38)
77
6.80 (1.70)
80
7.80 (2.90)
24.55
–1.00 (–1.74 to –0.26)
White et al. (AFIST II), 2003 (37)
77
7.88 (6.16)
83
11.30 (16.83)
1.06
–3.42 (–7.29 to 0.45)
Daoud et al., 1997 (32)
Total
716
100.00
665
–4
–2
Favors
Amiodarone
0
2
–0.63 (–1.03 to –0.23)
4
Favors
Placebo
AFIST ⫽ Atrial Fibrillation Suppression Trial.
334 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5
www.annals.org
Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery
we noted may have been due in part to the ␤-blocking
effects of amiodarone. Amiodarone also inhibits calcium
channels and may prevent vasospastic ischemia and infarction. Vasospasm has been described as a cause of perioperative myocardial infarction after coronary artery bypass
grafting with internal mammary arteries (46 – 48).
A recent large retrospective study indicated that atrial
fibrillation and atrial flutter are independent predictors of
inpatient and long-term mortality (8). Although the incidences of atrial fibrillation and atrial flutter and major cardiovascular events were decreased, amiodarone therapy did
not significantly alter the risk for death in our study. Mortality data in the studies included in our analysis were limited to inpatient death in 9 studies and death within 30
days of discharge in 1 study. Demonstration of a mortality
benefit might require data obtained from follow-up weeks
to months after discharge. It is also possible that modern
aggressive treatment of postoperative illnesses has already
had an important impact on the overall mortality rate,
limiting its correlation with postoperative ventricular
tachycardia or fibrillation, stroke, or myocardial infarction.
Whether a mortality benefit would be demonstrated in a
prospective study that is powered specifically to answer this
question remains uncertain.
Our study has several limitations. First, the incidence
of ventricular tachycardia or fibrillation, stroke, and myocardial infarction and length of stay were all secondary end
points in the trials in our analysis. These secondary end
points were predefined in some studies but not in others.
Definitions of these end points varied and were not explicitly stated in some trials. Second, the time span of the trials
was 1993 to 2003. Surgical techniques and postoperative
care improved during this period. Third, ␤-blockers, the
only agents whose effectiveness as prophylaxis is proven,
were not given to all patients or a uniform fraction of
patients in each trial. It is unclear whether the prophylactic
effects of amiodarone would have been blunted if all study
patients had received ␤-blockade. Finally, although all trials were randomized and double-blind, details of the randomization methods, the concealment of treatment allocation, and the handling of patients who dropped out or
were withdrawn from analysis were not always provided.
Our findings suggest that amiodarone prophylaxis reduces major cardiovascular morbidity and decreases length
of hospitalization after open-heart surgery. We believe that
all patients undergoing open-heart surgery should receive
prophylaxis with a ␤-blocker unless it is contraindicated, in
accordance with current guidelines (23). The value of routine use of amiodarone as an additional first-line prophylactic agent remains uncertain. To further evaluate the potential benefits of concomitant prophylaxis with both
␤-blockers and amiodarone, we recommend a multicenter,
randomized, double-blind trial with cardiovascular outcomes that compares amiodarone with placebo in patients
already receiving prophylaxis with a ␤-blocker. This study
should assess the optimal dosing regimen for amiodarone,
www.annals.org
Article
the degree of additional protection it provides beyond that
of ␤-blockade, whether amiodarone offers sufficient prophylaxis in patients intolerant of ␤-blockers, the true incidence of clinically significant adverse events due to amiodarone therapy, and whether amiodarone decreases the
incidence of myocardial infarction or death.
From Rush University Medical Center, Chicago, Illinois.
Potential Financial Conflicts of Interest: Consultancies: M.H. Kim,
R.G. Trohman (Guidant CRM Business Strategy Advisory Board); Honoraria: M.H. Kim, R.G. Trohman (St. Jude Medical, Inc., Guidant
CRM); Grants received: M.H. Kim, R.G. Trohman (St. Jude Medical,
Inc., Medtronic, Inc., Guidant CRM, Wyeth-Ayerst).
Requests for Single Reprints: Richard G. Trohman, MD, Rush Uni-
versity Medical Center, 1750 West Harrison, Suite 983 Jelke, Chicago,
IL 60612; e-mail, [email protected].
Current author addresses and author contributions are available at www
.annals.org.
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www.annals.org
Annals of Internal Medicine
Current Author Addresses: Dr. Aasbo: Medical College of Wisconsin,
Division of Cardiovascular Medicine, 9200 West Wisconsin Avenue,
Suite 5100, Milwaukee, WI 53226.
Drs. Lawrence, Krishnan, and Trohman: Rush University Medical Center, 1750 West Harrison, Suite 983 Jelke, Chicago, IL 60612.
Dr. Kim: Health Partners, Inc., 640 Jackson Street, Mail Stop 11102M,
St. Paul, MN 55101.
Author Contributions: Conception and design: J.D. Aasbo, R.G. Trohman.
Analysis and interpretation of the data: J.D. Aasbo, A.T. Lawrence, R.G.
Trohman.
Drafting of the article: J.D. Aasbo, K. Krishnan, M.H. Kim, R.G. Trohman.
Critical revision of the article for important intellectual content: J.D.
Aasbo, R.G. Trohman.
Final approval of the article: J.D. Aasbo, A.T. Lawrence, K. Krishnan,
M.H. Kim, R.G. Trohman.
Statistical expertise: J.D. Aasbo.
Administrative, technical, or logistic support: J.D. Aasbo.
Collection and assembly of data: J.D. Aasbo, A.T. Lawrence.
W-86 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5
www.annals.org
Appendix Table 1. Patient Characteristics, by Treatment Group*
Mean Age (SD), y
Study, Year
(Reference)
Butler et al., 1993
(30)
Daoud et al., 1997
(32)
Redle et al., 1999
(33)
Guarnieri et al., 1999
(31)
Treggiari-Venzi et al.,
2000 (35)
Giri et al., 2001 (34)
White et al., 2002
(29)
Yazigi et al., 2002
(36)
Yagdi et al., 2003
(38)
White et al., 2003
(37)
Men, %
History of Supraventricular
Tachycardia, %
Placebo
Group
History of Myocardial
Infarction, %
Amiodarone
Group
Placebo
Group
Amiodarone
Group
Placebo
Group
Amiodarone
Group
59 (7.6)
60 (9.1)
91.7
83.3
NS
57 (14)
61 (13)
68.8
66.7
63
64.5
83.6
81.4
None in past 6 mo
NS
63.3
63.9
74.1
76.8
None†
43
37.3
65‡
65§
87.8
84.3
2.0
3.9
59.2
31.4
72.7 (6.7)
72.6 (6.5)
72.5 (6.7)
72.5 (6.7)
78.3
78.9
74
74
13.3
13.0
6.0
6
44.2
43.9
25
25
60.6 (10.5)
60.6 (9.3)
64
66
None†
15
17
59.3 (8.9)
61.1 (9.6)
80.5
73.7
None†
41.6
51.3
66.8 (9.0)
64.9 (8.3)
76.8
74.7
2.6
24.7
26.5
7.8
6.7
2.4
Amiodarone
Group
Placebo
Group
50
56.7
31.3
30
* NS ⫽ not specified.
† Supraventricular tachycardia was an exclusion criterion.
‡ Range, 44 to 78 years.
§ Range, 37 to 88 years.
Appendix Table 2. Patient History, by Treatment Group*
Study, Year
(Reference)
Butler et al., 1993
(30)
Daoud et al., 1997
(32)
Redle et al., 1999
(33)
Guarnieri et al., 1999
(31)
Treggiari-Venzi et al.,
2000 (35)
Giri et al., 2001 (34)
White et al., 2002
(29)
Yazigi et al., 2002
(36)
Yagdi et al., 2003
(38)
White et al., 2003
(37)
History of Hypertension,
%
History of Diabetes
Mellitus, %
Amiodarone
Group
Placebo
Group
Amiodarone
Group
Amiodarone
Group
Placebo
Group
35
41.7
8.33
6.7
0.65 (0.12)
0.61 (0.15)
78.3
80
50
50
15.6
13.3
0.48 (0.12)
0.48 (0.13)
40.6
30
47.9
58.6
28.8
22.9
0.49
0.48
58.9
58.6
69.6
76.8
29.7
30.3
0.43 (0.28)
0.46 (0.26)
52.5
50.7
49
33.3
26.5
11.8
0.58 (0.14)
0.57 (0.13)
55.1
64.7
68.3
67.5
73
73
29.2
NS
36
0.423 (0.11)
0.436 (0.102)
0.431 (0.12)
0.431 (0.117)
70.8
87.7
74
91
40
38
25
27
⬍0.4 in 8 patients
⬍0.4 in 7 patients
67
66
50.6
65
26
31.3
NS
NS
Placebo
Group
Use of ␤-Blocker, %
Mean Left Ventricular Ejection Fraction
(SD)
Amiodarone
Group
Placebo Group
0.47 (0.99)
0.479 (0.104)
29.9
21.3
0.483 (0.123)
0.48 (0.127)
70.1
74.7
* NS ⫽ not specified.
www.annals.org
6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 W-87