Meta-Analysis Comparing Reported Frequency of Atrial Fibrillation After Acute
Coronary Syndromes in Asians Versus Whites
Gian M. Novaro, MDa,*, Craig R. Asher, MDa, Deepak L. Bhatt, MDb, David J. Moliterno, MDc,
Robert A. Harrington, MDd, A. Michael Lincoff, MDb, L. Kristin Newby, MDd,
James E. Tcheng, MDd, Amy P. Hsu, MSb, and Sergio L. Pinski, MDa
The development of atrial fibrillation (AF) in cardiac patients is multifactorial, including
not well defined genetic factors. To determine if Asian ethnicity is associated with the
development of AF in patients with coronary disease, a meta-analysis was conducted of
patient-level data from 7 prospective randomized clinical trials that prospectively collected
information on the development of AF: 3 trials in patients with ST-elevation myocardial
infarction (Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] I,
GUSTO III, and GUSTO V), 3 trials in patients with non–ST-elevation acute coronary
syndromes (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using
Integrilin Therapy [PURSUIT], Integrilin to Minimize Platelet Aggregation and Coronary
Thrombosis–II [IMPACT II], and Platelet IIb/IIIa Antagonist for the Reduction of Acute
Coronary Syndrome Events in a Global Organization Network [PARAGON A]), and 1 trial
in patients with both conditions (GUSTO IIb). A total of 94,785 patients were identified
(93,050 white, 1,735 Asian). At baseline, Asian patients were younger; had lower body mass
indexes; had a lower prevalence of female gender, previous angioplasty, and previous
coronary artery bypass grafting; and had a greater prevalence of diabetes compared with
white patients. The development of AF was lower in Asian than in white patients (4.7% vs
7.6%, p <0.001), while rates of ventricular tachycardia and fibrillation were similar in the
2 groups. In multivariate logistic regression analysis, Asian ethnicity was associated with
significantly lower rates of AF (odds ratio 0.65, 95% confidence interval 0.50 to 0.84, p ?
0.001) compared with white ethnicity. In conclusion, similar to previous studies showing a
lower incidence of AF in non-Caucasian populations, Asians experiencing acute ischemic
syndromes have a significantly lower frequency of AF compared with whites. Further study
is needed to investigate the mechanisms and potential genetic underpinnings behind this
association. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;101:506 –509)
To explore ethnic differences in the risk for atrial fibrillation
(AF) development, we conducted a meta-analysis of ran-
domized clinical trials and assessed the incidence of AF in
a large cohort of patients with acute coronary syndromes
Methods and Results
We identified all randomized controlled trials with patient-
level data housed at the Cleveland Clinic Cardiovascular
Coordinating Center that prospectively collected informa-
tion on the incidence of AF. Studies were selected if they
met the following criteria: (1) randomized controlled human
trials, (2) recorded white and Asian ethnicity in baseline
demographic data (subject self-reported), (3) involved sub-
jects with coronary artery disease and ACS, (3) study du-
ration ?30 days, and (4) incidence of AF during study
follow-up was reported. In total, 7 studies, all of which were
published in manuscript form, were included.1–7
We had access to the original patient-level data for all of
the clinical trials, and these data were combined to perform
the analyses. Categorical data are expressed as percentages,
and continuous data are expressed as mean ? SD. Frequen-
cies were analyzed using chi-square tests, and continuous
variables were analyzed using Wilcoxon’s 2-sample tests.
Within each study, we used a chi-square test to assess the
effect of ethnicity; odds ratios and 95% confidence intervals
were calculated. We used the Breslow-Day test to examine
the homogeneity of the odds ratios across the trials. A
summary odds ratio was also calculated using the Mantel-
Haenszel method. Logistic regression was performed to create
a final model. Stepwise variable selection techniques were
used, with a p value of 0.1 for entry. Backward and forward
selection were also tested. We used SAS version 9 (SAS
Institute Inc., Cary, North Carolina) to analyze all data. All
comparisons were considered significant at p ?0.05.
The characteristics of the selected studies are listed in
Table 1. Of the 7 studies, 4 included patients with ST-
elevation myocardial infarction,1–4and 4 included patients
with non–ST-elevation ACS.2,5–7There were 94,785 pa-
tients in the included studies. The follow-up period for all
studies was 30 days.
aDepartment of Cardiology, Cleveland Clinic Florida, Weston, Florida;
bDepartment of Cardiovascular Medicine, Cleveland Clinic, Cleveland,
Ohio;cGill Cardiovascular Institute, University of Kentucky, Lexington,
Kentucky; anddDuke Clinical Research Institute, Durham, North Carolina.
Manuscript received June 7, 2007; revised manuscript received and ac-
cepted September 21, 2007.
*Corresponding author: Tel: 954-659-5313; fax: 954-659-5292.
E-mail address: email@example.com (G.M. Novaro).
0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
Of the total patient pool, Asian ethnicity accounted for
2% (n ? 1,735) of the patient populations. The baseline
patient characteristics are listed in Table 2. On average,
Asian patients were younger, more likely male, were of
shorter height, and had lower body mass indexes and higher
heart rates at rest. Compared with white patients, Asians had
a lower prevalence of hypertension, hypercholesterolemia,
previous angioplasty, and coronary artery bypass grafting
but a greater prevalence of diabetes. In a subgroup of pa-
tients with baseline estimates of myocardial infarction size
and measures of ventricular function, Asians on average had
lower left ventricular ejection fractions and higher peak
creatine kinase levels (Table 2).
Table 3 lists the pooled odds ratios of incident AF on the
basis of ethnicity. Overall, the rates of incident AF ranged
from 1.4% to 10.5% during follow-up. The development of
Characteristics of randomized controlled trials
TrialPatient GroupNo. of Total PatientsWhitesAsians
GUSTO ? Global Use of Strategies to Open Occluded Coronary Arteries; IMPACT ? Integrilin to Minimize Platelet Aggregation and Coronary
Thrombosis; PARAGON ? Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PURSUIT ?
Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; STEMI ? ST-segment elevation myocardial infarction.
Baseline patient characteristics
Characteristic Whites Asians p Value
62 ? 12
57 ? 12
Body mass index (kg/m2)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
Heart rate (beats/min)
Previous percutaneous coronary intervention
Previous myocardial infarction
Previous coronary bypass
Ejection fraction (%)
Peak creatine kinase level (mg/dl)
86,380 (171 ? 9)
92,284 (79 ? 15)
86,324 (27 ? 5)
92,364 (132 ? 23)
91,788 (78 ? 14)
92,087 (75 ? 17)
1,542 (167 ? 8)
1,705 (72 ? 12)
1,541 (26 ? 4)
1,724 (131 ? 24)
1,714 (79 ? 15)
1,718 (77 ? 17)
Rates of incident atrial fibrillation by study
Trialn Whites AsiansOR (95% CI) p Value
Pooled percentages are based on total trial sample size weighted estimates.
CI ? confidence interval; OR ? odds ratio. Other abbreviations as in Table 1.
Arrhythmias and Conduction Disturbances/Asian Ethnicity and Atrial Fibrillation
AF was less frequent in Asians than whites (4.7% vs 7.6%,
p ?0.001), while rates of ventricular tachycardia and fibril-
lation were similar in the 2 groups (Table 4). The lower
incidence of AF in Asians was noted in all studies except
Integrilin to Minimize Platelet Aggregation and Coronary
Thrombosis–II (IMPACT II), in which only 19 Asian pa-
tients were recruited. There was a slight difference in the
association of ethnicity with AF among individual trials
(p ? 0.06, Breslow-Day test for homogeneity of odds ra-
tios), mainly represented by the odds-ratio difference in
IMPACT II. In multivariate logistic regression analysis,
Asian ethnicity was associated with a 35% lower rate of
incident AF (odds ratio 0.65, 95% confidence interval 0.50
to 0.84, p ? 0.001) compared with white ethnicity (Table 5).
This meta-analysis involving 94,785 patients (1,735 Asians)
indicates that ethnicity is strongly associated with the risk
for developing AF. Specifically, Asian ethnicity was asso-
ciated with a highly significant 35% lower incidence of AF
compared with white ethnicity. This relation remained after
adjusting for traditional demographic and cardiovascular
The association of ethnicity with cardiovascular out-
comes is increasingly recognized to extend beyond the
scope of socioeconomic and attitudinal differences related
to access, treatment, or referral patterns. Most notably, bi-
ologic explanations for discordant outcomes or responses to
treatment between black and white patients have been pro-
posed in populations with ACS, congestive heart failure,
and hypertension. The underpinnings of these disparities
include ethnicity-mediated effects on atherosclerosis, hemo-
stasis, and thrombolysis8,9and vascular reactivity.10,11
These early studies provide the basis for clinical trials such
as the African-American Heart Failure Trial (A-HeFT),
demonstrating the benefits of targeted therapy for black
patients with congestive heart failure.12
Ethnic differences in the prevalence of AF have been
reported in trials comparing whites with other ethnic
groups.13–16Despite the relatively small cohorts, a lower
prevalence of AF has been consistently observed in Asians
in various clinical arenas. In a general practice population,
the AF prevalence in Indo-Asians aged ?50 years was
0.6%.16In a multiethnic hospital registry, AF appeared to be
less prominently associated with nonhemorrhagic stroke in
Indo-Asians compared with whites.17In patients newly hos-
pitalized for heart failure, AF was less common in South
Asians compared with whites (15% vs 31%, p ? 0.0002).18
These findings reporting a lower prevalence of AF in Asians
in general practice, during an acute stroke, or when present-
ing with heart failure are consistent with our findings in a
Although the clinical factors associated with AF devel-
opment are well established, the pathologic abnormalities
leading to the arrhythmias are not. Hemodynamic, inflam-
matory, and autonomic influences on AF are known, al-
though the link to genetic processes is only now being
uncovered. Polymorphisms in renin-angiotensin system
genes have been characterized as predisposing to AF under
certain environmental conditions.19Familial forms of AF
have been described, with 3 different loci identified in Asian
families with genes encoding for potassium-related channel
function.20–22These studies establish some basis to suggest
that patients with structural heart disease may have genetic
predispositions to AF. The interplay between genetic sus-
ceptibility and biologic stressors may influence who devel-
ops AF and may be speculated as an explanation for differ-
ences in AF prevalence among ethnic groups.
We were unable to account for all variables that may
affect the development of AF, particularly specific to post-
ACS patients. Among the factors not accounted for are the
size of the left atrium, the level of inflammation, hemody-
namic parameters, and medication use. However, no data
are currently available for us to suspect that these variables
would differ among ethnic groups. The type, history, and
duration of AF were not determined in this study, and thus
a cause-effect relation cannot be confirmed. Particular at-
tention should be directed at the known heterogeneity of the
Asian population, for example, highlighted in the variation
of coronary heart disease risk among the Asian nations of
India, Korea, Vietnam, China, and Japan. Exacting the rea-
sons for these ethnic variations is challenging and ultimately
limits the use of ethnicity as a surrogate for genetics.
Rates of incident rhythm abnormalities
Rhythm AbnormalityWhitesAsians p Value
Second- or third-degree atrioventricular block
Multivariate logistic model for incident atrial fibrillation
VariableOR (95% CI)p Value
Previous myocardial infarction
Heart rate ?75 beats/min
Body mass index
Systolic blood pressure
Heart rate ?75 beats/min
Previous coronary bypass
Abbreviations as in Table 3.
The American Journal of Cardiology (www.AJConline.org)
1. The GUSTO Investigators. An international randomized trial compar-
ing four thrombolytic strategies for acute myocardial infarction.
N Engl J Med 1993;329:673–682.
2. The Global Use of Strategies to Open Occluded Coronary Arteries
(GUSTO) IIb Investigators. A comparison of recombinant hirudin with
heparin for the treatment of acute coronary syndromes. N Engl J Med
3. The Global Use of Strategies to Open Occluded Coronary Arteries
(GUSTO III) Investigators. A comparison of reteplase with alteplase
for acute myocardial infarction. N Engl J Med 1997;337:1118–1123.
4. Reperfusion therapy for acute myocardial infarction with fibrinolytic
therapy or combination reduced fibrinolytic therapy and platelet gly-
coprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet
5. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein
IIb/IIIa with eptifibatide in patients with acute coronary syndromes.
N Engl J Med 1998;339:436–443.
6. IMPACT II Investigators. Randomized placebo-controlled trial of ef-
fect of eptifibatide on complications of percutaneous coronary inter-
vention: IMPACT II. Lancet 1997;349:1422–1428.
7. The PARAGON Investigators. International, randomized, controlled
trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or
both in unstable angina. Circulation 1998;97:2386–2395.
8. Sane DC, Stump DC, Topol EJ, Sigmon KN, Clair WK, Kereiakes DJ,
George BS, Stoddard MF, Bates ER, Stack RS. Racial differences in
responses to thrombolytic therapy with recombinant tissue-type plas-
minogen activator. Increased fibrin(ogen)olysis in blacks. The Throm-
bolysis and Angioplasty in Myocardial Infarction Study Group. Cir-
9. Thomas LC, Giles TD, Stuckey WJ, Mautner RK, Iteld BJ. Racial
differences in platelet survival time in patients with symptomatic
coronary atherosclerosis. Arteriosclerosis 1983;3:138–140.
10. Weir MR, Gray JM, Paster R, Saunders E. Differing mechanisms of
action of angiotensin-converting enzyme inhibition in black and white
hypertensive patients. Hypertension 1995;26:124–130.
11. Lang CC, Stein CM, Brown RM, Deegan R, Nelson R, He HB, Wood
M, Wood AJ. Attenuation of isoproterenol-mediated vasodilation in
blacks. N Engl J Med 1995;333:155–160.
12. Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand
K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN, for the
African-American Heart Failure Trial Investigators. Combination of
isosorbide dinitrate and hydralazine in blacks with heart failure.
N Engl J Med 2004;351:2049–2057.
13. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV,
Singer DE. Prevalence of diagnosed atrial fibrillation in adults: na-
tional implications for rhythm management and stroke prevention: the
Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study.
14. Ruo B, Capra AM, Jensvold NG, Go AS. Racial variation in the preva-
lence of atrial fibrillation among patients with heart failure: the Epidemi-
ology, Practice, Outcomes and Costs of Heart Failure (EPOCH) study.
J Am Coll Cardiol 2004;43:429–435.
15. Kelley GP, Stellingworth MA, Broyles S, Glancy DL. Electrocardio-
graphic findings in 888 patients ?90 years of age. Am J Cardiol
16. Lip GY, Bawden L, Hodson R, Rutland E, Snatchfold J, Beevers DG.
Atrial fibrillation amongst the Indo-Asian general practice population:
the West Birmingham Atrial Fibrillation Project. Int J Cardiol 1998;
17. Conway DS, Lip GY. Ethnicity in relation to atrial fibrillation and
stroke (the West Birmingham Stroke Project). Am J Cardiol 2003;92:
18. Newton JD, Blackledge HM, Squire IB. Ethnicity and variation in
prognosis for patients newly hospitalized for heart failure: a matched
historical cohort study. Heart 2005;91:1545–1550.
19. Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, Moore
JH, Hsu KL, Tseng CD, Liau CS, Tseng YZ. Renin-angiotensin
system gene polymorphisms and atrial fibrillation. Circulation 2004;
20. Wall JD, Pritchard JK. Haplotype blocks and linkage disequilibrium in
the human genome. Nat Rev Genet 2003;4:587–597.
21. Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, Liang B, Lin J,
Liu Y, Liu B, et al. Identification of a KCNE2 gain-of-function
mutation in patients with familial atrial fibrillation. Am Hum Genet
22. Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y, Zhou Q,
Yang Y, Liu Y, Liu B, et al. A Kir2.1 gain-of-function mutation
underlies familial atrial fibrillation. Biochem Biophys Res Commun
Arrhythmias and Conduction Disturbances/Asian Ethnicity and Atrial Fibrillation