Interventions for prevention of post-operative atrial
fibrillation and its complications after cardiac
surgery: a meta-analysis
David C. Burgess1,2*, Michael J. Kilborn2, and Anthony C. Keech1,2*
1National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Level 5, Building F,
88 Mallett Street, Camperdown 2050, Sydney, NSW, Australia and2Department of Cardiology, Royal Prince Alfred Hospital,
Camperdown, Sydney, NSW, Australia
Received 6 February 2006; revised 21 July 2006; accepted 11 September 2006; online publish-ahead-of-print 2 October 2006
See page 2744 for the editorial comment on this article (doi:10.1093/eurheartj/ehl372)
Aims Atrial fibrillation (AF) is the most common complication after cardiac surgery. We aimed to
evaluate, by meta-analysis, all randomized trials testing interventions for preventing AF.
Methods and results Ninety-four trials of prevention of post-operative AF were identified, by standard
search methods, and analysed by standard meta-analysis techniques. All five commonly tested interven-
tions, beta-blockers (BBs), sotalol, amiodarone, magnesium, and atrial pacing, were effective in pre-
venting AF. The odds ratio (OR) for the effect of BB on the incidence of AF was 0.36 (95% CI
0.28–0.47, P , 0.001), but after trials confounded by post-operative non-study BB withdrawal were
excluded was 0.69 (95% CI 0.54–0.87, P ¼ 0.002). Sotalol reduced AF, compared with placebo (OR
0.34, 95% CI 0.26–0.45, P , 0.001) and compared with conventional BB (OR 0.42, 95% CI 0.26–0.65,
P , 0.001). Amiodarone reduced AF (OR 0.48, 95% CI 0.40–0.57, P , 0.001). Magnesium (Mg) also had
an effect (OR 0.57 95% CI 0.42–0.77) but there was significant heterogeneity (P , 0.001), partly
explained by concomitant BB. The effect of Mg with BB was less (OR 0.83, 95% CI 0.60–1.16). Pacing
reduced AF (OR 0.60, 95% CI 0.47–0.77, P , 0.001), despite wide variations in techniques. Only amio-
darone and pacing significantly reduced length of stay, average 20.60 days (95% CI 20.92 to 20.29)
and 21.3 days (95% CI 22.55 to 20.08), respectively. Collectively, all treatments analysed together
reduced stroke (OR 0.63, 95% CI 0.41–0.98). Amiodarone was the only intervention that alone signifi-
cantly reduced stroke rate (OR 0.54, 95% CI 0.30–0.95).
Conclusion All five interventions reduced the incidence of AF, though the effect of BBs is less than pre-
viously thought. The significant reductions in length of stay and stroke in meta-analysis suggest that
there are worthwhile benefits from aggressive prevention. Larger studies to confirm these clinical
benefits and evaluate their cost-effectiveness would be worthwhile.
Post-operative atrial fibrillation (AF) after cardiac surgery is
a growing problem. The rate of AF after cardiac surgery in
the 1970s was about 10%, and is now consistently at least
30%, and much higher in older patients or those undergoing
valve surgery.1,2Although AF was always considered a
problem, acknowledgment of AF as a potentially serious
arrhythmia has increased. There have been more than 100
trials, multiple meta-analyses, and three sets of practice
guidelines for prevention of post-operative AF in cardiac
surgery. Despite this, the mainstay of therapy remains beta-
blockers (BBs) alone, with only a modest influence on overall
rates of post-operative AF.
Development of AF immediately after coronary artery
bypass surgery (CABG) results in a longer stay in the
intensive care unit and in hospital,3–8together with a signifi-
cantly higher (two- to three-fold) risk of post-operative
stroke.4,8,9Post-operative AF has also been shown to inde-
pendently predict post-operative delirium and neurocogni-
Despite previous meta-analyses, there remains confusion
about the potential benefits of individual agents, making a
comprehensive updated review important; the present
meta-analysis adds another 4 years of research and several
thousand additional patients to the last comprehensive
The search was performed in accordance with the recommendations
of the Cochrane Collaboration, using Cochrane CENTRAL database,
Medline, Premedline, and Embase from the earliest achievable
date to December 2005. The initial search terms were ‘AF’ and
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: email@example.com
*Corresponding authors. Tel: þ61 2 9562 5000; fax: þ61 2 9565 1863.
E-mail address: firstname.lastname@example.org
European Heart Journal (2006) 27, 2846–2857
by guest on December 25, 2015
Inclusion criteria for studies
Although a variety of agents and procedures have been tested for
preventing AF, the aim of this meta-analysis was to include only
interventions tested in more than three trials: BBs (excluding
sotalol), sotalol, amiodarone, magnesium (Mg), and pacing.
Summary statistics for digoxin and calcium channel blockers
derived from previous meta-analyses are presented, as there have
been no additional trials of these agents since and there is
general acceptance that they are less effective interventions.13,14
Studies were included only if they met all of the following cri-
teria: (i) randomized controlled trials (RCTs) using placebo or
usual care (including BB) as the comparator; (ii) investigating the
prevention of post-operative AF in CABG or valve or combined
surgery as a primary aim of the trial; (iii) an adequately detailed
published method; and (iv) adequate data on efficacy published.
Double-blind and non-blinded studies were included. Papers pub-
lished in abstract form were reviewed but qualified only if they
included sufficient information to fulfil the above criteria. Trials
that did not qualify for the primary analysis as there were three
or fewer trials of that treatment strategy have been included in
a secondary table for comparison as were 19 studies of off-pump
coronary bypass surgery (OPCAB) in which AF rates were recorded
but were not a primary purpose of the trial.
Other outcome measurements that were extracted from the
analysis were AF requiring treatment, length of hospital stay
(LOS), mortality, major morbidity, bradycardia, withdrawal of treat-
ment, ventricular arrhythmias [tachycardia (VT) or fibrillation (VF)],
and stroke. Where information was not published, attempts were
made to contact authors.
Two reviewers independently performed the search (N.S., D.B.) and
two reviewers independently extracted the data from the published
sources (M.K., D.B.). Any discrepancies were resolved by consensus.
The occurrence of AF, AF requiring treatment, mortality, major
morbidity, bradycardia, treatment withdrawal, VT or VF, and
stroke were treated as dichotomous variables. LOS was treated as
a continuous variable, for which the sample size-weighted mean
difference was calculated as a difference between the mean
values of LOS in treatment and control groups.
Analyses were based on the intention-to-treat principle. Pooled
effect estimates and heterogeneity between studies were analysed
by use of the Revman 4.2 statistical package, with a random-effects
model with results presented as an odds ratio (OR) and 95% CIs.
Two-sided P-values ? 0.05 were regarded as inferring statistical
significance. Heterogeneity was assessed by means of the Cochran
Q heterogeneity test and considered significant when P ? 0.05.
Publication bias was assessed using Begg’s funnel plot and examined
for signs of asymmetry in the scatter plots of the treatment effects
from individual studies (on the x-axis) against standard error (SE) or
the variance of the effect estimate (y-axis) plotted on a logarithmic
scale. The shape of the plot should resemble a symmetrical inverted
funnel if publication bias is absent. Lack of symmetry, in particular
the absence of studies in the lower right quadrant (representing
small studies with a negative result) would raise suspicion that pub-
lication bias was present.
Ninety-four studies evaluating the prevention of post-
operativeAF were published
(Figure 1). Enrolment ranged from 36 to 1000 patients. All
studies included patients undergoing CABG or valve surgery
(Supplementary material, Table S1). Prevalence of back-
ground BB use varied but was higher in the more recent
trials. Some studies delivered prophylaxis pre-operatively;
in others, it was intra-operative or post-operative.
All trials used continuous ECG or Holter monitoring and
either daily ECGs or pre-discharge Holter monitoring.
Follow-up was usually restricted to the duration of hospital
stay, but was extended to 30 or 90 days in some trials.
There were 31 comparisons evaluating BB against placebo,
eight comparisons testing sotalol against placebo, together
with seven comparisons of sotalol with conventional beta
blockers in 14 trials, 18 comparisons of amiodarone with
placebo, 22 comparisons of magnesium with placebo, and
23 comparisons of overdrive pacing against back up pacing
in 14 trials (Table 1). There were 19 OPCAB trials in which
AF was reported but not a primary outcome of the trial
and 17 trials of other interventions with three or less trials
each (Table 2).
Thirty-one trials evaluated prevention of post-operative AF
by BB, comprising 4452 patients (Figure 2, Table 1).15–44
Despite showing an overall reduction in AF, there was signifi-
cant heterogeneity (P , 0.001) between the trials which
could not be explained by dose or drug. As such, it is inap-
propriate to pool all these study results together.
A significant amount of this heterogeneity was explained
by whether each trial required the withdrawal of non-study
BB in the control group. In those studies in which non-study
BB was withdrawn at the time of surgery in the control
group, the reduction in AF was much larger (OR 0.30, 95%
CI 0.22–0.40) compared with those trials allowing continu-
ation of non-study BB after surgery in the control group
(OR 0.69, 95% CI 0.54–0.87). Some of the residual hetero-
geneity was explained by the large variation between
trials in control group event rate (5–54%), with a higher
event rate tending to be associated with a larger effect
size. (Figure 2, Table 1, Supplementary material, Figure S1).
Fourteen trials evaluated sotalol for preventing post-
operative AF, comprising 2583 patients with 2622 patient
comparisons. Five trials used BB in the control arm,45–49
and seven used placebo control50–56and two trials had both
placebo and BB control arms43,44(Figure 2, Table 1, Supple-
mentary material, Figure S2).
Overall, AF was reduced from 33.7 to 16.9% (OR 0.37, 95%
CI 0.29–0.48). In the trials that compared it directly with
BB, sotalol reduced AF from 25.7 to 13.7% (OR 0.42, 95%
CI 0.26–0.65), showing that sotalol offers significant
additional protection over standard BB.
Significantly more patients were withdrawn from treatment
in the groups receiving sotalol than those receiving placebo
because of side effects (6.0 vs. 1.9%, P ¼ 0.004), predomi-
nantly hypotension and bradycardia. The difference though
was not significant when BB was the comparator (7.2 vs.
4.8%, P ¼ 0.25) (Figure 3, Supplementary material, Figure S8).
Eighteen trials (3295 patients), with a variety of dosing
strategies, have evaluated amiodarone for the prevention
of post-operative AF (Figure 2, Table 1, Supplementary
material, Figure S3).44,57–73Amiodarone reduced AF from
an average incidence of 33.2% in the control group to
19.8% (OR 0.48, 95% CI 0.40–0.57). In the amiodarone
Interventions for prevention of post-operative AF2847
by guest on December 25, 2015
trials, 3.4% in the control groups and 6.8% in the amiodarone
groups had bradycardia (OR 1.66, 95% CI 1.73–2.47). Also,
5.2% in the control groups and 2.2% in the amiodarone
groups had VT or VF (OR 0.45, 95% CI 0.29–0.69) (Figure 3,
Supplementary material, Figures S9 and S10).
Twenty-two trials (2896 patients) evaluated prevention of
post-operative AF by Mg (Figure 2, Table 1, Supplementary
material, Figure S4).19,70,74–95These trials varied greatly in
dose and timing of delivery. Despite showing an overall
reduction in AF (OR 0.57, 95% CI 0.42–0.77), there was
significant heterogeneity (P ¼ ,0.001) between trials not
explained by dose, meaning it is inappropriate to pool all
these studies together. Some of this heterogeneity was
explained by the concomitant use of BB; the largest effect of
magnesium was in the two trials with no use of BB (OR 0.05,
95% CI 0.02–0.16) and the smallest effect was in the trials
in which BB was recommenced post-operatively in both
treatment and control groups (OR 0.83, 95% CI 0.60–1.16).
comparisons evaluated overdrive pacing strategies for
prevention of post-operative AF (Figure 2, Table 1,
Supplementary material, Figure S5).62,96–108
were all small (21–160 patients). The overall effect of
pacing was a reduction in AF from 34.8 to 24.6% (OR 0.60,
95% CI 0.47–0.77). Bi-atrial pacing had the only individually
significant result, with the greatest effect size, reducing AF
from an average of 35.3% in the control group to 17.7% in the
paced group (OR 0.44, 95% CI 0.31–0.64). Right atrial pacing
among 1586 patients with 1885 patient
Flow chart of study selection.
2848 D.C. Burgess et al.
by guest on December 25, 2015
reduced AF from 33.1% in the control group to 27.5% in the
paced group (not significant, OR 0.74, 95% CI 0.48–1.12).
Left atrial (LA) pacing or Bachmann’s bundle pacing
reduced AF from 37.5% in the control group to 30.2% in
the paced group (not significant, OR 0.70, 95% CI 0.46–1.07).
Digoxin was not found to be effective for AF prevention in
the Kowey meta-analysis published in 199213(OR 0.97, 95%
CI 0.62–1.49). No further studies have been identified or
published since that analysis (Figure 2, Table 1).
Trials included in primary analysis
Intervention TrialsComparatorPatientsOR 95% CI
Placebo þ no post-operative
non-study BBs ‘BB withdrawal’
Placebo þ post-operative
non-study BB recommenced
‘No BB withdrawal’
Placebo þ BB use not stated
BB or placebo
Placebo þ no BB allowed pre- or
Placebo þ no BB post-operatively
Placebo þ restart of non-study BB
Placebo þ BB use not stated
3 11630.690.54–0.87 0.0020.72
LA or Bachmann’s bundle
Calcium channel blockersd
aJanssen et al.43and Auer et al.44had both BB and placebo control arms, number of patients represents number of patient comparisons.
bGoette et al.,96Daoud et al.,97Newman et al.,98Fan et al.,102Greenberg et al.,103and Gerstenfeld et al.105had two or more active treatment arms
in trials; number of patients represent number of patient comparisons.
cKowey et al.13
dWijeysundera et al.14
Randomized controlled trials otherwise ineligible for the primary analysis
On-pump with AF rate ?45%
On-pump with AF rate ?30 , 45%
On-pump with AF rate ,30%
Beta-blocker or placebo
Ventral cardiac denervation
Preservation anterior fat pad
N-3 fatty acids
Intrapericardial blake drain
GIK, glucose–insulin–potassium; T3, tri-iodothyronine.
Interventions for prevention of post-operative AF2849
by guest on December 25, 2015
Calcium channel blockers
Similarly, there has been little new research on calcium
channel blockers (CA) since 2000. The 2003 Wijeysundera
meta-analysis14provides the most up to date results.
Overall, there was no significant effect on supraventricular
tachycardias (SVT), OR 0.73, 95% CI 0.48–1.12 but with
significant heterogeneity (P ¼ 0.004). Subgroup analyses
showed that non-dihydropyridines significantly reduced
SVT (OR 0.62, 95% CI 0.41–0.93) but still with significant
heterogeneity (P ¼ 0.03), whereas dihydropyridines non-
significantly increased SVT (OR 2.69, 95% CI 0.57–12.64)
(Figure 2, Table 1).
Trials excluded from primary analysis
Nineteen OPCAB109–126trials reported rates of AF, but did
not meet the entry criteria for inclusion in the meta-analysis,
as AF was not a primary endpoint of these trials. As such,
monitoring, definitions and concomitant therapies vary
Effect of all interventions on post-operative occurrence of AF.
2850 D.C. Burgess et al.
by guest on December 25, 2015
(P , 0.001) which is partly explained by the baseline rates
of AF in the control groups. There was a larger effect in
those trials with an AF rate in the control group of ?45%
(OR 0.20, 95% CI 0.11–0.37) and a non-significant effect in
the lowest risk group with AF ,30% (OR 0.80, 95% CI
0.63–1.02) (Table 2, Supplementary material, Figure S11
and Table S2).
Seventeen trials127–143did not meet the entry criteria for
inclusion in the meta-analysis as the interventions were not
tested in more than three trials but provide an overview of
treatments, some that have historical interest only such as
quinidine and some interventions that are early in the inves-
tigative cycle and that will require confirmatory studies
(Table 2, Supplementary material, Figure S12 and Table S3).
andthe trials havesignificant heterogeneity
Length of stay
seven sotalol44,48,50,51,53,55,56trials (3 trials44,56,62tested
multiple interventions). Only amiodarone and pacing had a
significant effect on LOS (Figure 4, Supplementary material,
Figure S6). Amiodarone reduced LOS (20.60 95% CI 20.92
to 20.29) compared with control. Pacing reduced LOS
(21.3 days 95% CI 22.55 to 20.08) compared with control.
Risk of stroke
Twenty-five trials (5479 patients)15,35,40,44,48,51,57,58,61–64,
66–69,71–73,76,93,97,102,104,105reported on the incidence of
post-operative stroke (Figure 5, Supplementary material,
Figure S7). No individual trial has shown less stroke, but
with all trials of all treatments combined, reported stroke
rate averaged 1.9% in the control group and 1.1% with treat-
ment (OR 0.63, 95% CI 0.41–0.98). Amiodarone was the only
single intervention that showed a significantly reduced
stroke rate, from 2.4% in the control group to 1.2% in the
treatment group (OR 0.54, 95% CI 0.30–0.95). There was
no obvious indication that this finding was subject to import-
ant publication bias based on assessment of a funnel plot
(Figure 6, Supplementary material, Figure S7).
Systematic meta-analysis is an important tool to identify the
effects of treatment and differences in effects between sub-
groups of patients beyond the reach of individual clinical
trials.144This meta-analysis is unique in clarifying the
status of AF prophylaxis in contemporary clinical practice
by identifying the confounding effect of BB withdrawal in
the trials of both BBs and magnesium; additionally, it is
the first to find a significant advantage of sotalol over stan-
dard BBs and identify a significant overall reduction in both
stroke and LOS with prophylaxis. As such, this meta-analysis
The routine use of prophylaxis for preventing AF after
cardiac surgery has been adopted slowly, partly because of
a perception that post-operative AF is of minor clinical con-
sequence and partly because of the small size of trials,
which until recently were unable to document significant
benefits on clinical outcomes even when pooled. The
absence of comprehensive safety data has also probably
slowed clinical uptake.
Reliance on recommencing BB alone after surgery leaves
a significant number of patients at risk of post-operative
AF. The previous reports of BB effectiveness in preventing
AF have been overestimated for contemporary practice
due to grouping of heterogenous trials. The trials included
subjects with a wide variety of background BB use. The
estimates were confounded by the grouping of trials requir-
ing non-study BB withdrawal after surgery (increasing
control group AF rate and subsequently the effect size of
study BB) with studies allowing continuation of non-study
BB (it is thought that acute BB withdrawal increases the
risk of post-operative AF beyond that of BB-naive patients).
The effectiveness of Mg has previously been similarly over-
estimated because of pooling all trials together which in
this analysis was found to be inappropriate due to hetero-
geneity, some of which is due to concomitant use of BB. In
the Mg trials that most closely reflect current clinical prac-
tice, in which BB were recommenced post-operatively,
there is no significant reduction in AF (OR 0.83, 95% CI
0.60–1.16) attributable to Mg.
review the currentpolicy
Effect of sotalol and amiodarone on adverse events.
Interventions for prevention of post-operative AF2851
by guest on December 25, 2015
The lower rate of AF when cardiopulmonary bypass is not
used (OPCAB) could logically relate to reduced systemic
inflammation or reduced trauma to the atrium; but as it
was not uniformly studied in the OPCAB trials, it may alter-
natively relate to confounding effects of less inotrope
requirement, earlier recommencement of BBs, or shorter
time on electrocardiographic monitoring. However, as
more trials are performed in this area, it may provide
important insights into the causes of post-operative AF.
Several investigative therapies (Table 2) also look promising
but may be subject to considerable publication bias.
The other major barrier to the use of more potent prophy-
laxis is the perception that post-operative AF does not affect
other clinical outcomes; this meta-analysis provides the
strongest evidence to date that reduction in AF can
improve clinical outcomes, specifically reducing LOS and
Although the number of stroke events in the meta-analysis
was small and the reduction in stroke with AF prophylaxis
must be viewed as hypothesis-generating requiring further
study, it suggests that the risk of post-operative stroke
attributable to AF is sufficiently large for AF prevention to
reduce it. There was no evidence that publication bias
explained this finding (Figure 6).
Patients after cardiac surgery have several factors leading
to a higher risk of thrombo-embolic stroke than non-surgical
patients. A thrombotic milieu is often present post-
operatively, with impaired left ventricular systolic and dias-
tolic function, subsequent high LA pressure, dilation of LA
and the LA appendage (LAA), decreased LAA velocities,
increased stasis, and enhanced potential for thrombus for-
mation. These changes are aggravated when post-operative
AF occurs and lessened when AF can be prevented.
Anticoagulation is sometimes contraindicated and may be
underused. Other plausible mechanisms that may be import-
ant in the reduction of stroke by AF prophylaxis are preven-
tion of low output states resulting from rapid AF and
preventionof low output
formation from complicating VT and VF.
Much larger RCTs would be needed to determine whether
stroke reduction with more potent AF prevention can be
Effect of all interventions on post-operative stroke.
OR. The scatter indicates minimal publication bias (see methods).
Funnel plot of studies reporting stroke outcomes showing SEs of
Effect of all interventions on hospital LOS.
2852D.C. Burgess et al.
by guest on December 25, 2015
Our meta-analysis suggests that if sufficiently potent
methods are used, both the risk of stroke and LOS may be
reduced in patients undergoing cardiac surgery. This could
translate to real clinical benefits; for example, if amiodar-
one is as effective as the analysis suggests treating 1000
similar patients would prevent 134 episodes of AF, 30 epi-
sodes of sustained VT, and 12 strokes at the cost of 34 epi-
sodes of bradycardia but saving about 600 hospital days.
This meta-analysis is limited by the lack of complete avail-
ability of all relevant data. Data on stroke rates, VT and
VF, treatment withdrawal, and LOS were not available in
many included studies. As such, there may be reporting
bias in these outcomes. Although no intervention affected
mortality due to the low overall death rates, a difference
cannot be excluded. In addition, many studies failed to
collect or report on comprehensive safety outcomes.
This meta-analysis supports the present recommendation
that BBs are not withdrawn in the post-operative period,
but suggests,in contrast
dations,145–147that in those at high risk of AF, BB will not
offer great protection when used alone. There is little com-
pelling evidence that BBs are more effective than other
therapies or reduce LOS or morbidity. In fact, the largest
study of BB showed only a modest reduction in AF incidence,
from 39 to 31%, with no change in LOS or costs (though
control rates of BB use were probably high reflecting con-
temporary clinical practice but diluting the effect size).15
In the comparisons of BB and sotalol, the rate of AF in the
BB group was high: 25.9% and significantly reduced by
sotalol. Magnesium may offer little or no additional benefit
to those using BB therapy and we do not recommend it for
prophylaxis in this setting. Amiodarone trials give the most
comprehensive information on morbidity, and collectively
now show a decrease in AF, LOS, ventricular arrhythmias,
and stroke at the expense of increased bradycardia. In con-
trast to a recent meta-analysis148that focuses only on amio-
darone, we feel that there is now sufficient evidence to
state that amiodarone gives additive protection when used
with BB, as there is no heterogeneity across the amiodarone
trials, despite widely varying rates of BB use, from 2573to
100%.71Additionally, the largest trial of amiodarone64also
showed a significant reduction in AF in a pre-specified sub-
group analysis of subjects on peri-operative BB drug
therapy (15.3 vs. 25.1%, P ¼ 0.03). Pacing also showed a sig-
nificant reduction in AF and LOS and is the only strategy that
was applied exclusively post-operatively without negative
inotropic or chronotropic effects. The best strategy or
drug dose to follow cannot be concluded from this analysis
and is clearly an area for further research. The future of
AF prevention is the addition of these more potent strat-
egies to routine BB continuation, although the overall
benefits with comprehensive safety data should ideally be
confirmed in large-scale multicentre RCTs.
to previous recommen-
Supplementary material is available at European Heart
We would like to thank the staff of the NHMRC Clinical Trials Centre
for assistance with this study, in particular Nicole Smith (NS) and
Rhana Pike. This study was supported by the National Health and
Medical Research Council Clinical Trials Centre, University of
Sydney, and through a research scholarship to David Burgess, by
the Cardiac Society of Australia and New Zealand.
Conflict of interest: The authors have no conflicts of interest to
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