Mathew JP, Fontes ML, Tudor IC, Ramsay J, Duke P, Mazer CD, Barash PG, Hsu PH, Mangano DT, for the Investigators of the Ischemia Research and Education Foundation
and the Multicenter Study of Perioperative Ischemia Research Group . A Multicenter Risk Index for Atrial Fibrillation After Cardiac Surgery. JAMA. 2004;291(14):1720-1729. doi:10.1001/jama.291.14.1720
Author Affiliations: Multicenter Study of Perioperative Ischemia Research Group and Department of Anesthesiology, Duke University Medical Center, Durham, NC (Dr Mathew); Department of Anesthesiology, Weill Medical College of Cornell University, New York, NY (Dr Fontes); Ischemia Research and Education Foundation, San Francisco, Calif (Drs Tudor, Hsu, and Mangano); Department of Anesthesiology, Emory University Hospital, Atlanta, Ga (Dr Ramsay); Department of Anesthesiology, University of Manitoba, Winnipeg (Dr Duke); Department of Anesthesiology, University of Toronto, Toronto, Ontario (Dr Mazer); and the Department of Anesthesiology, Yale University School of Medicine, New Haven, Conn (Dr Barash).
Context Atrial fibrillation is a common, but potentially preventable, complication
following coronary artery bypass graft (CABG) surgery.
Objectives To assess the nature and consequences of atrial fibrillation after CABG
surgery and to develop a comprehensive risk index that can better identify
patients at risk for atrial fibrillation.
Design, Setting, and Participants Prospective observational study of 4657 patients undergoing CABG surgery
between November 1996 and June 2000 at 70 centers located within 17 countries,
selected using a systematic sampling technique. From a derivation cohort of
3093 patients, associations between predictor variables and postoperative
atrial fibrillation were identified to develop a risk model, which was assessed
in a validation cohort of 1564 patients.
Main Outcome Measure New-onset atrial fibrillation after CABG surgery.
Results A total of 1503 patients (32.3%) developed atrial fibrillation after
CABG surgery. Postoperative atrial fibrillation was associated with subsequent
greater resource use as well as with cognitive changes, renal dysfunction,
and infection. Among patients in the derivation cohort, risk factors associated
with atrial fibrillation were advanced age (odds ratio [OR] for 10-year increase,
1.75; 95% confidence interval [CI], 1.59-1.93); history of atrial fibrillation
(OR, 2.11; 95% CI, 1.57-2.85) or chronic obstructive pulmonary disease (OR,
1.43; 95% CI, 1.09-1.87); valve surgery (OR, 1.74; 95% CI, 1.31-2.32); and
postoperative withdrawal of a β-blocker (OR, 1.91; 95% CI, 1.52-2.40)
or an angiotensin-converting enzyme (ACE) inhibitor (OR 1.69; 95% CI, 1.38-2.08).
Conversely, reduced risk was associated with postoperative administration
of β-blockers (OR, 0.32; 95% CI, 0.22-0.46), ACE inhibitors (OR, 0.62;
95% CI, 0.48-0.79), potassium supplementation (OR, 0.53; 95% CI, 0.42-0.68),
and nonsteroidal anti-inflammatory drugs (OR, 0.49; 95% CI, 0.40-0.60). The
resulting multivariable risk index had adequate discriminative power with
an area under the receiver operating characteristic (ROC) curve of 0.77 in
the validation sample. Forty-three percent (640/1503) of patients who had
atrial fibrillation after CABG surgery experienced more than 1 episode of
atrial fibrillation. Predictors of recurrent atrial fibrillation included
older age, history of congestive heart failure, left ventricular hypertrophy,
aortic atherosclerosis, bicaval venous cannulation, withdrawal of ACE inhibitor
or β-blocker therapy, and use of amiodarone or digoxin (area under the
ROC curve of 0.66). Patients with recurrent atrial fibrillation had longer
hospital stays and experienced greater infectious, renal, and neurological
complications than those with a single episode.
Conclusions We have developed and validated models predicting the occurrence of
atrial fibrillation after CABG surgery based on an analysis of a large multicenter
international cohort. Our findings suggest that treatment with β-blockers,
ACE inhibitors, and/or nonsteroidal anti-inflammatory drugs may offer protection.
Atrial fibrillation after CABG surgery is associated with important complications.
A number of advances in anesthetic and surgical techniques have reduced
risk in patients undergoing cardiac surgery.1 However,
postoperative atrial fibrillation remains common, with an incidence that is
consistently reported to range between 27% and 40%, with little change over
the past 2 decades.2- 6 Previous
reports have suggested that atrial fibrillation is associated with an increased
incidence of congestive heart failure (CHF), renal insufficiency, and stroke,6,7 which prolong hospitalization2,6,8,9 and increase
rates of rehospitalization after discharge.8- 11
The intraoperative and postoperative periods are potentially stressful
for the heart with extremes in response affecting reperfusion, inflammation,
hemostasis, and excitotoxicity. Most previous studies of postoperative atrial
fibrillation have primarily focused on chronic disease and risk factors prior
to surgery. In addition, many studies are based on single-institution data,
which limits generalizability. Therefore, using data gathered prospectively
from an international multicenter population, we assessed the nature and consequences
of atrial fibrillation and developed and validated a comprehensive risk index
that defines patients at risk for atrial fibrillation after coronary artery
bypass graft (CABG) surgery.
The Ischemia Research and Education Foundation and the Multicenter Study
of Perioperative Ischemia Epidemiology II is a prospective and longitudinal
study, which includes 5436 patients from 70 hospitals on 4 continents (17
countries) scheduled for CABG surgery between November 1996 and June 2000.
Following institutional review board approval, each center was to enroll 100
patients prospectively according to a systematic sampling scheme among all
patients undergoing CABG surgery with or without valve repair or replacement
using cardiopulmonary bypass. Eligible patients were aged 18 years or older;
willing to provide informed consent and participate in a preoperative interview;
and were not simultaneously enrolled in another clinical trial.
More than 7500 fields of data per patient were collected by independent
investigators throughout each enrolled patient's index hospitalization; treating
physicians were blinded to all research data. Data included demographic, historical,
clinical, laboratory, and electrocardiographic information as well as resource
use and adverse outcome. All data fields for each patient were queried centrally
for completeness and accuracy, with all changes documented prior to database
closure. All patient data were entered using ORACLE (Redwood Shores, Calif)
at the central analysis unit.
All outcomes were prespecified, defined by protocol, and determined
by independent investigators blinded to the study question. Postoperative
atrial fibrillation was defined by entry into the case report form or by detection
on the postoperative electrocardiogram of atrial fibrillation or flutter.
A diagnosis of myocardial infarction (MI) was made if there were either new
Q waves (Minnesota codes 1-1-1 to 1-2-7); new persistent ST-segment or T-wave
changes (Minnesota codes 4-1, 4-2, 5-1, 5-2, or 9-2) and elevated values for
the myocardial band isoenzyme of creatine kinase; or evidence of acute MI
on autopsy. A diagnosis of heart failure was made if a ventricular assist
device was used; if continuous inotropic support was required for at least
24 hours; or if there was evidence of heart failure on autopsy. Stroke was
diagnosed on the basis of a focal or global defect on physical examinaton,
tomographic scan, magnetic resonance imaging, or autopsy. A decline in score
on the Mini-Mental State Examination of 3 points or more and an increase in
score on the National Institutes of Health Stroke Scale score of 4 points
or more was considered significant. Renal dysfunction was defined by a serum
creatinine level of at least 2.0 mg/dL (177 µmol/L), accompanied by
an increase of at least 0.70 mg/dL (61.9 µmol/L) from baseline. Renal
failure was defined by either renal dysfunction and dialysis or evidence of
renal failure on autopsy. Atrial fibrillation was considered to have preceded
a complication if it occurred prior to the first day of diagnosis of the complication.
Because clinical decisions were not controlled by study protocol, all
patients qualifying within the prespecified enrollment period were entered.
Of the 5436 patients enrolled, 372 were excluded because the patient withdrew
from the study prior to its completion (n = 32), death prior to surgery (n
= 2), cancelled or rescheduled surgery (n = 97), a change in scheduled surgical
procedure (n = 132), inadvertent enrollment in another study (n = 11), incomplete
data (n = 87), or incomplete blood sampling, shipping, or storage (n = 11).
Patients were also excluded because they concurrently underwent additional
procedures (n = 256), such as carotid endarterectomy or had chronic atrial
fibrillation (n = 151). A total of 4657 patients were included in this analysis.
Potential predictors of atrial fibrillation were chosen based on a review
of the literature. Candidate variables prior to surgery included age; sex;
right coronary artery stenosis of 90% or higher; ejection fraction; left atrial
enlargement; left ventricular hypertrophy; left ventricular dilation based
on a combination of methods including echocardiography, electrocardiography,
and/or ventriculography; aortic atherosclerosis based on echocardiogram; hypokalemia;
a history of atrial fibrillation, valvular disease, CHF, vascular disease,
neurological event, diabetes, any MI, hypertension or chronic obstructive
pulmonary disease (COPD); prior CABG surgery or valve surgery; and current
treatment with β-blockers, angiotensin-converting enzyme (ACE) inhibitors,
calcium channel blockers, amiodarone, or nonsteroidal anti-inflammatory drugs
Potential intraoperative predictors of atrial fibrillation included
valve surgery, bicaval cannulation, pulmonary vein venting (a surgical procedure
performed during cardiopulmonary bypass to keep the left ventricle empty),
moderate or severe aortic atherosclerosis, duration of cross-clamp and cardiopulmonary
bypass, myocardial and cardiopulmonary bypass temperature, volume and type
of cardioplegia (blood, crystalloid), retrograde cardioplegia, adenosine or
procainamide in cardioplegia, ejection fraction by transesophageal echocardiography,
asynchronous atrial or atrioventricular pacing, occurrence of atrial fibrillation
or ventricular tachycardia or fibrillation, and treatment with β-blockers,
calcium channel blockers, magnesium, amiodarone, digoxin, aminocaproic acid,
aprotinin, NSAIDs, or inotropic drugs.
Postoperative predictors of atrial fibrillation included asynchronous
atrial or atrioventricular pacing, intra-aortic balloon pump use, Q-wave MI,
pericarditis, CHF, hypokalemia (<3.5 mEq/L), hypomagnesemia (<2 mg/dL), β-blocker
or ACE-inhibitor withdrawal, and treatment with inotropic drugs, β-blockers,
ACE inhibitors, calcium channel blockers, NSAIDs, amiodarone, or supplementation
with potassium or magnesium. For patients experiencing postoperative atrial
fibrillation, postoperative variables were defined by their occurrence before
the onset of atrial fibrillation.
For categorical variables, a 2-tailed χ2 or Fisher exact
test was used to compare patients with and without postoperative atrial fibrillation.
For continuous variables, a t test or Wilcoxon rank
sum test was applied. To evaluate the effect of atrial fibrillation alone
on length of intensive care unit (ICU) stay and postsurgical hospitalization,
875 patients with complications other than atrial fibrillation were excluded.
Patients with complications were included in all other analyses.
To develop an atrial fibrillation risk index, patients were assigned
to a derivation cohort (first 66.4% of patients enrolled at each site; n =
3093) or to a validation cohort (last 33.6% enrolled; n = 1564). Because enrollment
continued for 3.5 years, this sampling scheme provided temporal validity.
Univariate associations between potential predictors and atrial fibrillation
in the derivation cohort were investigated using the χ2 test,
Fisher exact test, and logistic regression modeling. All variables significant
at a nominal 2-tailed P≤.20 were then entered
into multivariable logistic models using a combination stepwise selection
method. A preoperative model was first developed using only preoperative factors.
Subsequently, intraoperative factors were added to create an intraoperative
model, followed by addition of postoperative factors to develop a final model.
Model entry and retention criteria were set at P≤.20
and P≤.01. The final model was evaluated using
the Hosmer-Lemeshow goodness-of-fit test12 and
the area under the receiver operating characteristic (ROC) curve in which
an area of more than 0.75 represents a model with good discriminate power.
To develop relative weights for the predictors in the Multicenter Study
of Perioperative Ischemia risk index, the parameter estimates of the final
logistic model were multiplied by 10 and rounded to the nearest integer.13 The relative weight was then assigned to each binary
predictor, as well as to each age category (10-year increments). The Multicenter
Study of Perioperative Ischemia Atrial Fibrillation risk index for each patient
was calculated by summing the relative weights across the predictors present
for a particular patient. Four risk groups were preplanned based on quartiles.
Because both the observed and the predicted incidence rates were similar between
the second and the third quartiles, 3 risk groups were defined. The low risk
group contained scores below the 25th percentile; the medium risk group contained
scores in the 25th to 75th percentile; and the high risk group contained scores
higher than the 75th percentile.
In secondary analyses, similar sequential steps and techniques were
adopted for the development of a risk index for recurrent (>1 episode during
the index hospitalization) atrial fibrillation. Model entry and retention
criteria were set at P≤.20 and P<.05. All analyses were performed using SAS statistical software
(version 8.2, SAS Institute Inc, Cary, NC).
In the entire study population, the incidence of postoperative atrial
fibrillation after CABG surgery and prior to hospital discharge was 32.3%
(1503/4657). This incidence was similar among patients in the United States
(33.7%), Canada (36.6%), Europe (34.0%), United Kingdom (31.6%), and the Middle
East (41.6%), but the incidence was lower in South America (17.4%) and Asia
(15.7%) (P<.001). Atrial fibrillation was first
detected by continuous monitoring (telemetry) in 76.8% (1155/1503); by 12-lead
electrocardiogram in 17.5% (263/1503); and by physical examination in 12.8%
(193/1503). Forty-three percent of patients (640/1503) experienced more than
1 episode of atrial fibrillation. Atrial fibrillation was most common on postoperative
day 2 while recurrence was most common on postoperative day 3 with more than
60% of initial recurrence occurring within 2 days of first onset (Figure 1). However, only 22% of patients
(326/1503) experienced more than 2 episodes.
The incidence of postoperative atrial fibrillation was similar in both
the derivation cohort (31.6%; 976/3093) and the validation cohort (33.7%;
527/1564). In the derivation cohort, 43.7% (426/976) experienced multiple
episodes of atrial fibrillation, and 40.6% (214/527) in the validation cohort
had multiple episodes. Hypertension and COPD were more frequent in the validation
cohort, while preoperative calcium-channel blockade was more common in the
derivation cohort (Table 1).
Among patients in the derivation cohort, significant independent predictors
of atrial fibrillation were advanced age, history of atrial fibrillation or
COPD, valve surgery, and withdrawal of β-blockers or ACE inhibitors (Table 2). Conversely, treating patients
with β-blockers preoperatively and postoperatively or postoperatively
only was associated with a reduced incidence of atrial fibrillation. Similarly,
treatment with ACE inhibitors preoperatively and postoperatively and postoperative
potassium supplementation and NSAID administration were associated with a
reduced incidence of atrial fibrillation. The area under the ROC curve for
this model was 0.78, and the Hosmer-Lemeshow goodness-of-fit test was not
significant for lack of fit (P = .36). A risk score
less than 14 was considered low risk, scores of 14 to 31 were considered medium
risk; and scores higher than 31 were considered high risk (Table 2 and Figure 2).
Comparison of the predictive ability of the model revealed that the incidence
of atrial fibrillation was similar in the derivation and validation cohorts
stratified across the 3 risk groups (Figure
3). The area under the ROC curve when applying the final model in
the validation cohort was 0.77.
Among patients who experienced postoperative atrial fibrillation in
the derivation cohort, advanced age, left ventricular hypertrophy, moderate
or severe aortic atherosclerosis, bicaval venous cannulation, and withdrawal
of ACE inhibitor or β-blocker therapy were significant predictors of
recurrent atrial fibrillation, while a history of CHF and use of amiodarone
or digoxin was associated with a lower odds of recurrence (Table 3). The Hosmer-Lemeshow goodness-of-fit test for the model
yielded a score of 10.97 (P = .20) and the area under
the ROC curve was 0.69. The area under the ROC curve when applying this model
in the validation cohort was 0.66. A risk score of less than 9 was considered
low risk; scores of 10 to 22 were medium risk; and scores higher than 22 were
high risk (Table 3).
The initial episode was treated pharmacologically in 76.9% (1156/1503)
of patients, or electrically by cardioversion in 3.7% (56/1503), and by overdrive
pacing in 2.1% (31/1503). No therapy was rendered in 17.3% (260/1503). Digoxin
was the most common medication administered during the initial episode of
atrial fibrillation, whereas amiodarone, β-blockers, and calcium channel
blockers were commonly added for subsequent episodes. Anticoagulation using
heparin was started after atrial fibrillation in 56.2% (845/1503) while 17.6%
(265/1503) received warfarin.
Atrial fibrillation was associated with a greater incidence of subsequent
postoperative complications including cognitive changes, renal dysfunction,
and infection. This incidence rate was higher in patients with multiple episodes
of atrial fibrillation than in patients with a single episode (Table 4). The incidence of a composite outcome (encephalopathy,
decline in Mini-Mental State Examination score, increase in National Institutes
of Health Stroke Scale score, renal dysfunction, renal failure, pneumonia,
mediastinitis or deep sternal wound infection, sepsis, harvest site infection,
vascular catheter infection, and genitourinary infection) in the patients
with atrial fibrillation was 22.6% (340/1503) compared with 15.4% (483/3154)
in the patients without atrial fibrillation. Multivariable analysis showed
that atrial fibrillation was significantly and independently associated (odds
ratio, 1.19 [95% confidence interval, 1.0-1.43]; P =
.049) with this composite outcome, after adjusting for propensity of risk
factors for patients to develop atrial fibrillation. Inhospital mortality
in patients with atrial fibrillation was 4.7% (71/1503) compared with 2.1%
(66/3154) in patients without atrial fibrillation (P<.001).
Patients with atrial fibrillation had longer ICU and hospital stays
(Table 5). The median difference
in postsurgical hospitalization was 2 days. Once discharged from the ICU,
patients with atrial fibrillation were also more likely to return to the ICU.
After the onset of atrial fibrillation, patients experienced a greater level
of testing with computerized axial tomography and ultrasonography. Thirty-five
percent of patients (527/1503) with atrial fibrillation were discharged to
an extended care facility compared with 28% (882/3154) without atrial fibrillation
(P<.001). Patients with more than 1 episode of
atrial fibrillation experienced longer ICU (mean [SD], 65.1 [85.6] vs 51.3
[64.6] hours; median [interquartile range], 43 [22.4-71.4] vs 28.3 [21.3-64.0]
hours; P = .001) and hospital (mean [SD], 11.2 [7.5]
vs 9.9 [5.6] hours; median [interquartile range], 9 [8-12] vs 9 [7-11] days; P<.001) stays than those with a single episode.
Despite ongoing efforts to decrease its occurrence, postoperative atrial
fibrillation remains a frequent complication of CABG surgery. In a large,
multicenter, international cohort, we found that the incidence of postoperative
atrial fibrillation was remarkably consistent (approximately 32%) across most
regions of the world. Second, the majority of the initial episodes of atrial
fibrillation occurred within the first 3 days after CABG surgery. Third, atrial
fibrillation recurred in 43% of patients with more than 60% of initial recurrence
occurring within 2 days of the first episode. Fourth, postoperative atrial
fibrillation increased hospital resource use and was associated with greater
neurological, renal, and infectious complications. Fifth, patients with recurrent
atrial fibrillation experienced a greater complication rate and had longer
hospital stays than those with a single episode. Sixth, advancing age, prior
history of atrial fibrillation or COPD, valve surgery, and withdrawal from
ACE inhibitor or β-blocker therapy were associated with an increased
risk of atrial fibrillation. Seventh, use of β-blockers or ACE inhibitors
preoperatively and postoperatively or use of β-blockers, potassium supplementation,
and NSAIDs postoperatively only was associated with a reduced risk of atrial
fibrillation. Eighth, advancing age, left ventricular hypertrophy, significant
aortic atherosclerosis, bicaval venous cannulation, and withdrawal of ACE
inhibitor or β-blocker therapy were significant predictors of recurrent
atrial fibrillation. Finally, a history of CHF and use of amiodarone or digoxin
were associated with a lower risk of recurrence.
The Multicenter Study of Perioperative Ischemia atrial fibrillation
risk index can be used to accurately assess risk of atrial fibrillation among
patients undergoing CABG surgery.
To the best of our knowledge, this is the first study to capture the
precise day of onset of both atrial fibrillation and postoperative complications,
allowing for examination of the temporal relationship between atrial fibrillation
and those complications occurring after the onset of atrial fibrillation.
This is also the first study to document the frequency of atrial fibrillation
recurrence and its significant association with a greater complication rate
as well as longer length of stay. Encephalopathy, cognitive decline, increase
in National Institutes of Health Stroke Scale score, renal dysfunction and
failure, and infection occurred more frequently in patients with recurrent
atrial fibrillation but not those with a single episode. Endothelial dysfunction
and abnormalities in the prothombotic or hypercoagulable state seen in patients
with paroxysmal atrial fibrillation may contribute to this increased risk.14 Although the stroke rate in our study was not increased
in patients with atrial fibrillation, this finding should be interpreted with
caution. The lack of association may reflect the current clinical practice
of aggressively treating patients at highest risk for stroke (ie, those with
persistent atrial fibrillation) with anticoagulants.
When preoperative factors are considered, advanced age has been the
most consistent predictor of postoperative atrial fibrillation.2,4- 6 Our
results show that every 10-year increase in age is associated with a 75% increase
in the odds of developing atrial fibrillation; thus, on the basis of age alone,
anyone older than 70 years is considered to be at high risk for developing
atrial fibrillation. Age-related changes in atrial connective tissue, dilation,
and nonuniform anisotropic conduction may account for this increased risk.15 However, these changes in atrial substrate may not
be related to CABG surgery itself because a higher rate of atrial fibrillation
in older patients is also seen in the nonsurgical Framingham population.16
Changes in the atrial substrate are also a plausible explanation for
the importance of a history of atrial fibrillation in its postoperative reoccurrence.
The risk of atrial fibrillation is likely to increase when there are preoperative
changes in the atrial substrate and when sensitivity to factors that previously
triggered atrial fibrillation persist.17 The
final preoperative predictor of atrial fibrillation (prior COPD) has been
study reveals that chronic lung disease produces a 43% increase in the odds
of developing atrial fibrillation. A larger sample size of patients with COPD
may account for this variation from prior research. While the pathogenesis
of atrial fibrillation in patients with COPD is unclear, it is likely multifactorial
and partially related to the increased P-wave dispersion present in patients
Valve surgery was the only intraoperative variable associated with an
increased risk of atrial fibrillation. The incidence of atrial fibrillation
after valve surgery typically exceeds that in patients undergoing coronary
revascularization alone,4,6,20 with
the greater susceptibility believed to result from structural and hemodynamic
abnormalities such as left atrial enlargement, pathological changes from rheumatic
heart disease, increased left atrial pressure, and surgical trauma.20 Although left atrial enlargement was not a predictor
in our study, pathological changes associated with valvular heart disease
at a cellular level are poorly described in our study of clinical predictors.
It is possible that these pathological changes are more important than the
surgical procedure itself.
Postoperative administration of several medications and/or withholding
of medications was associated with an alteration in the occurrence of atrial
fibrillation. Withdrawal of β-blocker therapy in the immediate postoperative
period resulted in a 91% increase in the odds of developing atrial fibrillation.
However, when β-blockers were given preoperatively and postoperatively,
or even initiated postoperatively only, the odds were significantly reduced
by between 51% to 68%. Despite guidelines recommending that early postoperative
administration of β-blockers should be standard therapy for the prevention
of atrial fibrillation,21 only 52% of the patients
were treated with β-blockers postoperatively; and in 24%, β-blockers
were actually withdrawn from therapy. Sympathetic activation or an exaggerated
response to adrenergic stimulation may be an important trigger for postoperative
Similarly, ACE inhibitor therapy initiated before and after surgery
was associated with a lower risk of atrial fibrillation, while withdrawal
from therapy was associated with an increased risk. Recent reports have suggested
that atrial fibrillation is associated with an activation of the atrial angiotensin
system.23,24 Atrial expression
of ACE is increased in patients with atrial fibrillation,23 possibly
leading to angiotensin II–dependent atrial fibrosis and regulation of
angiotensin II–receptor subtypes.24 Moreover,
ACE inhibitor therapy has been shown to reduce the occurrence of atrial fibrillation
after MI.25 Pretreatment with ACE inhibitors
decreases the relapse rate of atrial fibrillation after cardioversion.26 ACE inhibition might thus alter the pathophysiological
substrate of the atria to decrease the occurrence of atrial fibrillation.
Withdrawal of ACE inhibitor therapy may, in turn, up-regulate receptor subtypes
and promote the structural and electrical remodeling of the atria.23
Cardiopulmonary bypass is associated with an ischemia-reperfusion injury,
inducing a complex inflammatory response. Inflammatory changes have been reported
in patients with atrial fibrillation ranging from the presence of inflammatory
infiltrates in atrial biopsies27 to increased
concentrations of C-reactive protein.28,29 Acute
inflammation, particularly the development of pericarditis, is thought to
alter atrial coupling and lead to transient structural or electrical changes
that predispose patients to atrial fibrillation.30 In
our study, postoperative pericarditis was not a significant predictor of atrial
fibrillation and was diagnosed in only 1.2% of patients. However, administering
NSAIDs was associated with a reduction in the odds of developing atrial fibrillation,
suggesting that inflammation may contribute to the pathogenesis of postoperative
To the best of our knowledge, our study is also the first to examine
the predictors of recurrent in-hospital atrial fibrillation, which was observed
commonly in older patients with aortic atherosclerosis and left ventricular
hypertrophy. The latter has been shown to correlate with atrial fibrillation
and systolic hypertension, which, in turn is associated with increased aortic
rigidity from aortic atherosclerosis.10,16,31 The
interaction between these comorbid conditions and atrial fibrillation, whether
genetic, inflammatory, or physiological, are poorly defined and often coexist,
such that pathophysiological distinctions become difficult. The inverse relationship
between CHF and recurrent atrial fibrillation is both surprising and unclear.
On the other hand, our findings of increased recurrence of atrial fibrillation
following withdrawal of β-blocker or ACE inhibitor therapy and diminished
risk of recurrence from treatment with amiodarone or digoxin strengthen existing
reports and recommendations for management of atrial fibrillation32 and, more important, for lowering morbid and fatal
perioperative vascular events. Lastly, bicaval venous cannulation (most often
performed for mitral valve surgery) may predispose toward recurrent atrial
fibrillation as a consequence of greater surgical injury.
Limitations to our study include its observational design. Thus, the
effects of medications are likely to be overestimated and confounded by treatment
bias wherein patients with greater comorbidities may be less likely to receive β-blockers
or NSAIDs. However, the described associations of atrial fibrillation with
drug therapy were independent of postoperative markers of illness severity
such as CHF, MI, and inotropic therapy. Second, episodes of atrial fibrillation
may have been missed because of the lack of continuous electrocardiographic
monitoring, although the recorded incidence of atrial fibrillation is comparable
with other published reports. Third, systematic electrolyte concentrations
were not obtained. Thus, the potential for significant temporal variation
in serum electrolyte concentrations in patients after CABG surgery makes it
difficult to accurately categorize electrolyte abnormalities. Fourth, although
our study revealed no effect of amiodarone in reducing postoperative atrial
fibrillation, a larger sample of patients treated with preoperative amiodarone
is needed. Finally, the model for recurrent atrial fibrillation only has moderate
discriminative power (area under the ROC curve, 0.66) and thus, our findings
need to be confirmed prior to the widespread application of this risk index.
In summary, the Multicenter Study of Perioperative Ischemia atrial fibrillation
risk index may be used to identify patients for whom prophylactic therapy
might be most effective,33 to optimize current
therapeutic regimens, and to define patient selection criteria for future
interventional trials. Our findings indicate that discontinuation of certain
cardiovascular medications may be unwise and that ACE inhibitors and/or NSAIDs
may offer protection against postoperative atrial fibrillation. Patients with
recurrent atrial fibrillation are at greater risk for postoperative complications
and aggressive intervention should be considered.