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Effect of Atrial Fibrillation on Outcome in Patients With Known or Suspected Coronary Artery Disease Referred for Exercise Stress Testing
Effect of Atrial Fibrillation on Outcome in Patients With Known or Suspected Coronary Artery Disease Referred for Exercise Stress Testing Alberto Bouzas-Mosquera, MDa,*, Jesús Peteiro, MD, PhDa, Francisco J. Broullón, MSb, Nemesio Álvarez-García, MDa, Victor X. Mosquera, MDc, Sheyla Casas, MDa, Alberto Pérez, MDa, Elizabet Méndez, MDa, and Alfonso Castro-Beiras, MD, PhDa,d The association of atrial fibrillation (AF) with coronary artery disease (CAD) remains controversial. In addition, the relation of AF to myocardial ischemia and outcomes in patients with known or suspected CAD referred for exercise stress testing has been poorly explored. In this study, 17,100 patients aged >50 years with known or suspected CAD who underwent exercise electrocardiography (n ⴝ 11,911) or exercise echocardiography (n ⴝ 5,189) were evaluated. End points were all-cause mortality, nonfatal myocardial infarction, and coronary revascularization. Overall, 619 patients presented with AF at the time of the tests. Patients with AF who had interpretable electrocardiograms had a lower likelihood of exercise-induced ischemic ST-segment abnormalities (adjusted odds ratio 0.51, 95% confidence interval 0.34 to 0.76, p ⴝ 0.001), and those with AF who underwent exercise echocardiography had a lower likelihood of new or worsening exercise-induced wall motion abnormalities (adjusted odds ratio 0.62, 95% confidence interval 0.44 to 0.87, p ⴝ 0.006). During a mean follow-up period of 6.5 ⴞ 3.9 years, 2,364 patients died, 1,311 had nonfatal myocardial infarctions, 1,615 underwent percutaneous coronary intervention, and 922 underwent coronary artery bypass surgery. The 10-year mortality rate was 43% in patients with AF compared to 19% in those without AF (p <0.001). In multivariate analysis, AF remained an independent predictor of all-cause mortality (adjusted hazard ratio 1.45, 95% confidence interval 1.20 to 1.76, p <0.001), but not of nonfatal myocardial infarction or coronary revascularization. In conclusion, despite being associated with an apparently lower likelihood of myocardial ischemia, AF was an independent predictor of all-cause mortality in patients with known or suspected CAD referred for exercise stress testing. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1207–1211) Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, and its prevalence is increasing with the aging of the population.1–3 Patients with AF may present with symptoms suggestive of myocardial ischemia, such as chest discomfort due to a rapid and irregular heart rate, which do not necessarily translate into the presence of significant coronary artery disease (CAD).4 Although many of these patients are referred for stress testing, the prevalence of AF in patients with proved CAD seems to be low,5,6 and the association between AF and CAD remains controversial.7 In contrast, although there are data to support that the combination of AF and CAD confers a worse prognosis,6,8 the association of AF with outcomes has not been well characterized in patients with known or suspected CAD referred for exercise stress testing. Thus, our aim was to assess the relations of AF to myocardial ischemia, coronary angiographic results, all-cause mortality, and coronary Departments of aCardiology, bInformation Technology, and cCardiac Surgery, Hospital Universitario A Coruña, A Coruña; and dRed Temática de Investigación Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain. Manuscript received November 4, 2009; revised manuscript received and accepted December 14, 2009. *Corresponding author: Tel: 34-981178184; fax: 34-981178258. E-mail address: [email protected] (A. Bouzas-Mosquera). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.037
ischemic events in patients with known or suspected CAD undergoing treadmill exercise testing. Methods This was a retrospective analysis of a prospectively collected database. From March 1995 to March 2008, we evaluated 17,100 consecutive patients with known or suspected CAD aged ⱖ50 years who were referred for first treadmill stress testing at our institution. Of them, 11,911 underwent exercise electrocardiography and 5,189 underwent exercise echocardiography. Demographic, clinical, and stress test data were entered in a dedicated database at the time of the tests. All patients gave informed consent before testing, and the study was approved by our local research ethics committee. Blood pressure, heart rate, and a 12-lead electrocardiogram were obtained at baseline and at each stage of the exercise protocol. The electrocardiogram was considered interpretable in the absence of left bundle branch block, paced rhythm, preexcitation, left ventricular hypertrophy, repolarization abnormalities, or treatment with digoxin. Patients underwent a treadmill exercise test until they reached an end point, including physical exhaustion, severe angina, exercise-induced ST-segment deviation ⬎2 mm, significant www.AJConline.org
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Table 1 Baseline characteristics of the 17,100 patients Variable
Men Age (years) Diabetes mellitus Hypertension Hypercholesterolemia Smokers Family history of coronary artery disease Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary bypass Left bundle branch block Typical angina pectoris  blockers Calcium channel blockers Digoxin Nitrates Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers Diuretics Left ventricular ejection fraction at rest*
All Patients (n ⫽ 17,100)
10,101 (59.1%) 64.3 ⫾ 8.2 2,675 (15.6%) 8,442 (49.4%) 7,619 (44.6%) 3,694 (21.6%) 2,032 (11.9%) 2,963 (17.3%) 1,550 (9.1%) 508 (3%) 600 (3.5) 1,015 (5.9%) 2,098 (12.3%) 2,555 (14.9%) 387 (2.3%) 3,983 (23.3%) 4,169 (24.4%) 1,259 (7.4%) 56.3 ⫾ 10.0
AF
p Value
No (n ⫽ 16,481)
Yes (n ⫽ 619)
9,713 (58.9%) 64.1 ⫾ 8.1 2,585 (15.7) 8,138 (49.4%) 7,430 (45.1%) 3,614 (21.9%) 1,975 (12%) 2,871 (17.4%) 1,506 (9.1%) 484 (2.9%) 574 (3.5%) 983 (6%) 1,998 (12.1%) 2,447 (14.8%) 141 (0.9%) 3,792 (23%) 3,944 (23.9%) 1,085 (6.6%) 56.6 ⫾ 9.7
388 (62.7%) 69.2 ⫾ 7.6 90 (14.5%) 304 (49.1%) 189 (30.5%) 80 (12.9%) 57 (9.2%) 92 (14.9%) 44 (7.1%) 24 (3.9%) 26 (4.2%) 32 (5.2%) 100 (16.2%) 108 (17.4%) 246 (39.7%) 191 (30.9%) 225 (36.3%) 174 (28.1%) 52.8 ⫾ 12.0
0.06 ⬍0.001 0.44 0.90 ⬍0.001 ⬍0.001 0.04 0.10 0.08 0.18 0.34 0.41 0.003 0.07 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
Data are expressed as number (percentage) or as mean ⫾ SD. * Available in the subset of 5,189 patients who underwent exercise echocardiography.
arrhythmias, severe hypertension (systolic blood pressure ⬎240 mm Hg or diastolic blood pressure ⬎110 mm Hg), or severe hypotensive response (decrease ⱖ20 mm Hg in systolic blood pressure from baseline value). Exercise protocols included the Bruce (95.6%), modified Bruce (2%), Naughton (1.1%), and other (1.4%) protocols. In patients with interpretable rest electrocardiograms, positive exercise electrocardiographic results were defined as the development of ST-segment deviation ⱖ1 mm that was horizontal or sloping away from the isoelectric line 80 ms after the J point. In the subset of patients who underwent treadmill exercise echocardiography, imaging was performed at rest, at peak exercise, and immediately after exercise, as previously described.9,10 Peak exercise images were acquired with the patient still exercising, when signs of exhaustion were present or an end point was achieved. The transducer was firmly placed on the apical and parasternal areas, and pressure was applied to the patient’s back with the left hand to decrease the relative movement between the transducer and the patient’s body. Peak and postexercise images were obtained using a continuous imaging acquisition system. The best quality images corresponding to each view were selected for comparison with those acquired at rest. Positive exercise echocardiographic results were defined as the appearance of new or worsening exercise-induced wall motion abnormalities, except worsening from akinesia to dyskinesia and isolated hypokinesia of the inferobasal segment. Coronary angiography was performed at the discretion of the referring physician. A significant coronary stenosis was defined as a ⱖ50% luminal stenosis of the left main coronary artery or a ⱖ70% stenosis of any other major epicardial coronary artery. Coronary angiographic results ⬍90 days after the tests were recorded.
Follow-up data were obtained by review of hospital databases, medical records, death certificates, and telephone interviews. End points were all-cause mortality, nonfatal myocardial infarction, and coronary revascularization procedures. We did not evaluate cardiac mortality, because the ascertainment of the cause of death may be liable to bias and misclassification.11 Categorical variables were compared between groups using the chi-square test and are reported as percentages. Continuous variables were assessed using the unpaired Student’s t test or the Mann-Whitney U test as appropriate and are reported as mean ⫾ SD. Survival free of the end point of interest was estimated using the Kaplan-Meier method, and survival curves were compared using the log-rank test. Multivariate logistic regression analyses were performed to determine the adjusted odds ratios for the association of AF with myocardial ischemia on exercise electrocardiography and exercise echocardiography, as well as with the presence of angiographically proved CAD. Adjusted hazard ratios for the association of AF with the end points were estimated using Cox proportional-hazard models. Whenever appropriate, multivariate analyses were adjusted by age, gender, diabetes mellitus, hypertension, hypercholesterolemia, smoking habit, family history of CAD, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass grafting, typical angina, left bundle branch block,  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, nitrates, calcium channel blockers, digoxin, diuretics, exercise-induced chest pain, exercise electrocardiographic results, METs, peak systolic blood pressure, and percentage of maximum age-predicted heart rate. Multivariate analyses performed in the subgroup of patients who underwent exercise echocardiography were
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Table 2 Exercise data obtained during the tests Variable
All Patients (n ⫽ 17,100)
Peak systolic blood pressure (mm Hg) Peak heart rate (beats/min) % of age-predicted maximum heart rate Peak rate–pressure product (⫻103 mm Hg · beats/min) Exercise-induced chest pain METs
175.9 ⫾ 31.1 143.3 ⫾ 21.1 92.0 ⫾ 12.8 25.3 ⫾ 6.2 2,133 (12.5%) 8.8 ⫾ 2.8
AF
p Value
No (n ⫽ 16,481)
Yes (n ⫽ 619)
176.6 ⫾ 30.9 142.9 ⫾ 20.5 91.5 ⫾ 12.3 25.4 ⫾ 6.2 2,086 (12.7%) 8.9 ⫾ 2.9
156.8 ⫾ 30.6 156.9 ⫾ 28.8 103.9 ⫾ 18.7 24.7 ⫾ 6.9 47 (7.6%) 6.7 ⫾ 2.8
⬍0.001 ⬍0.001 ⬍0.001 0.03 ⬍0.001 ⬍0.001
Data are expressed as mean ⫾ SD or as number (percentage). Table 3 Association of atrial fibrillation with ischemic electrocardiographic changes, ischemia on exercise echocardiography, and angiographically proved coronary artery disease Variable Positive exercise electrocardiographic results Positive exercise echocardiographic results Angiographically proved CAD
Adjusted Odds Ratio (95% CI)
p Value
0.51 (0.34–0.76)
0.001
0.62 (0.44–0.87)
0.006
0.66 (0.33–1.35)
0.26
also adjusted by rest left ventricular ejection fraction and exercise-induced wall motion abnormalities. A p value ⬍0.05 was considered significant. Statistical analyses were carried out using SPSS version 15.0 (SPSS, Inc., Chicago, Illinois). Results Of the 17,100 patients, 619 (3.6%) presented with AF at the time of the exercise stress tests. Baseline characteristics of the 17,100 patients are listed in Table 1, and exercise data are listed in Table 2. A total of 15,324 patients had interpretable rest electrocardiograms. Of them, 2,516 patients (16.4%) developed significant exercise-induced ST-segment abnormalities, and the latter occurred less frequently in patients with AF (12.0% vs 16.5% in patients without AF, p ⫽ 0.028). In contrast, among the subgroup of 5,189 patients who underwent exercise echocardiography, 1,778 patients (34.3%) developed new or worsening wall motion abnormalities during exercise, which also were less likely in patients with AF (22.2% vs 35.1% in patients without AF, p ⬍0.001). These associations remained significant after adjustment for other potential confounders (Table 3). Overall, 1,668 patients underwent coronary angiography ⬍90 days after the treadmill tests. Of them, 1,237 (77.7%) showed significant coronary stenoses. The likelihood of angiographically proved CAD in patients with AF who underwent coronary angiography (52.0%) was significantly less than that of patients without AF (77.7%) (p ⬍0.001). However, these results did not remain significant after covariate adjustment (Table 3). During a mean follow-up period of 6.5 ⫾ 3.9 years, 2,364 patients died, 1,311 had nonfatal myocardial infarctions, 1,615 underwent percutaneous coronary intervention,
Figure 1. All-cause mortality curves in patients with and without AF.
and 922 underwent coronary artery bypass surgery. The 10-year mortality rate was 43% in patients with AF compared to 19% in patients without AF (p ⬍0.001; Figure 1). Figure 2 shows the relation of AF with all-cause mortality stratified according to exercise electrocardiographic and exercise echocardiographic results. In multivariate analysis, AF was an independent predictor of all-cause mortality risk, but it did not remain significantly associated with nonfatal myocardial infarction or coronary revascularization (Table 4). The association of AF with mortality remained consistent even when the subgroup of patients who underwent exercise echocardiography was selectively evaluated and rest left ventricular ejection fraction and exercise-induced wall motion abnormalities were included in the multivariate analysis (adjusted hazard ratio 1.54, 95% confidence interval [CI] 1.19 to 1.98, p ⬍0.001). In the subset of patients without histories of CAD, those with AF and interpretable rest electrocardiograms had a lower likelihood of ischemic electrocardiographic changes during the tests (adjusted odds ratio 0.53, 95% CI 0.33 to 0.84, p ⫽ 0.007); in addition, those patients who underwent exercise echocardiography who had AF also had a lower likelihood of echocardiographic myocardial ischemia (adjusted odds ratio 0.57, 95% CI 0.37 to 0.89, p ⫽ 0.01). The
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Figure 2. All-cause mortality curves in patients with and without AF according to (A) exercise electrocardiographic (ExECG) and (B) exercise echocardiographic (ExEcho) results. Table 4 Prognostic value of atrial fibrillation in patients with known or suspected coronary artery disease Variable All-cause mortality Nonfatal myocardial infarction Coronary revascularization
Adjusted Hazard Ratio (95% CI)
p Value
1.45 (1.20–1.76) 0.77 (0.53–1.11) 1.05 (0.79–1.39)
⬍0.001 0.16 0.84
10-year mortality rate in patients without history of CAD who had AF was higher than that of patients without AF (39.9% vs 16.4%, p ⬍0.001). As in the overall population, AF remained an independent predictor of mortality in this subgroup of patients (adjusted hazard ratio 1.55, 95% CI 1.23 to 1.96, p ⬍0.001). Discussion This study is the first to assess the association of AF with myocardial ischemia, CAD, and outcomes in patients with known or suspected CAD referred for exercise stress testing. Despite being associated with an apparently lower likelihood of myocardial ischemia, as assessed by exercise electrocardiography and exercise echocardiography, AF was an independent predictor of all-cause mortality in these patients. However, we did not observe a significant, independent association with nonfatal coronary events. Whether the likelihood of obstructive CAD or future coronary events is increased in patients with AF remains controversial.7,12 Some studies have reported either a low prevalence of AF in patients with CAD5,6,13 or a lack of association between AF and CAD.14 Others, however, have suggested a link between these 2 entities. In patients without histories of CAD, Nucifora et al15 found a higher prevalence of obstructive CAD, as assessed by multislice computed tomography, in those patients with AF. In the same line, Pierre-Louis et al16 observed that patients with diabetes mellitus who had AF had a higher prevalence of significant CAD than those in sinus rhythm. In contrast, Marte et al8 found that AF was associated with a lower prevalence of angiographically determined CAD, suggesting that AF may produce symptoms leading to referral for coronary angiography in the absence of significant CAD. In this latter study, however, patients with AF were paradoxically at increased
risk for future coronary events. Miyasaka et al17 also found a high incidence of coronary events in patients with AF without histories of CAD. In our study, the apparent association between AF and a lower likelihood of angiographically proved CAD in the subgroup of patients referred for coronary angiography did not remain significant after multivariate adjustment. In addition, we failed to find a significant association between AF and future nonfatal coronary events. Notwithstanding these controversies, previous reports agree that the combination of AF and CAD portends a higher mortality risk.6,8 Our study complements and expands on these observations by demonstrating a significant association of AF with all-cause mortality in patients with known or suspected CAD referred for exercise stress testing. This study had the limitations inherent in its retrospective and observational design. Only a small proportion of patients in our cohort underwent coronary angiography ⬍90 days after the tests; thus, our results regarding the association of AF with coronary angiographic findings may be affected by referral bias. In addition, the increased chronotropic response to exercise in patients with AF18 and the beat-to-beat variations in the length of cardiac cycles might affect the accuracy of noninvasive stress tests.19 Moreover, the diagnostic and prognostic values of exercise echocardiography in patients with AF have not yet been specifically evaluated. Thus, further studies addressing this issue are warranted. 1. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469 – 473. 2. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285:2370 –2375. 3. Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol 2001;37:371–378. 4. Veloso HH, Diniz MC. Are physicians recommending coronary angiographies more than necessary in atrial fibrillation? Int J Cardiol 2000;76:85– 88. 5. Haddad AH, Prchkov VK, Dean DC. Chronic atrial fibrillation and coronary artery disease. J Electrocardiol 1978;11:67– 69. 6. Cameron A, Schwartz MJ, Kronmal RA, Kosinski AS. Prevalence and significance of atrial fibrillation in coronary artery disease (CASS registry). Am J Cardiol 1988;61:714 –717.
Coronary Artery Disease/Atrial Fibrillation, CAD, and Outcomes 7. Wheeldon N. Coronary heart disease and atrial fibrillation. Studies have not shown a causal relation. BMJ 1996;312:641– 642. 8. Marte T, Saely CH, Schmid F, Koch L, Drexel H. Effectiveness of atrial fibrillation as an independent predictor of death and coronary events in patients having coronary angiography. Am J Cardiol 2009; 103:36 – 40. 9. Bouzas-Mosquera A, Peteiro J, Álvarez-Garcia N, Broullon FJ, Mosquera VX, Garcia-Bueno L, Ferro L, Castro-Beiras A. Prediction of mortality and major cardiac events by exercise echocardiography in patients with normal exercise electrocardiographic testing. J Am Coll Cardiol 2009;53:1981–1990. 10. Peteiro J, Bouzas-Mosquera A, Broullon FJ, Garcia-Campos A, Pazos P, Castro-Beiras A. Prognostic value of peak and post-exercise treadmill exercise echocardiography in patients with known or suspected coronary artery disease. Eur Heart J 2010;31:187–195. 11. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death in clinical research: time for a reassessment? J Am Coll Cardiol 1999; 34:618 – 620. 12. Lokshyn S, Mewis C, Kuhlkamp V. Atrial fibrillation in coronary artery disease. Int J Cardiol 2000;72:133–136. 13. Galrinho A, Gomes JA, Antunes E, Catarino C, da Silva N, Ferreira R, Quininha J, Rato JA. Atrial fibrillation and coronary disease [article in Portuguese]. Rev Port Cardiol 1993;12:1037–1940.
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14. Onundarson PT, Thorgeirsson G, Jonmundsson E, Sigfusson N, Hardarson T. Chronic atrial fibrillation— epidemiologic features and 14 year follow-up: a case control study. Eur Heart J 1987;8:521–527. 15. Nucifora G, Schuijf JD, Tops LF, van Werkhoven JM, Kajander S, Jukema JW, Schreur JH, Heijenbrok MW, Trines SA, Gaemperli O, Turta O, Kaufmann PA, Knuuti J, Schalij MJ, Bax JJ. Prevalence of coronary artery disease assessed by multislice computed tomography coronary angiography in patients with paroxysmal or persistent atrial fibrillation. Circ Cardiovasc Imaging 2009;2:100 –106. 16. Pierre-Louis B, Aronow WS, Palaniswamy C, Singh T, Weiss MB, Kalapatapu K, Pucillo AL, Monsen CE. Obstructive coronary artery disease in high-risk diabetic patients with and without atrial fibrillation. Coron Artery Dis 2009;20:91–93. 17. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Seward JB, Iwasaka T, Tsang TS. Coronary ischemic events after first atrial fibrillation: risk and survival. Am J Med 2007;120:357–363. 18. Hilliard AA, Miller TD, Hodge DO, Gibbons RJ. Heart rate control in patients with atrial fibrillation referred for exercise testing. Am J Cardiol 2008;102:704 –708. 19. Poldermans D, Bax JJ, Elhendy A, Sozzi F, Boersma E, Thomson IR, Jordaens LJ. Long-term prognostic value of dobutamine stress echocardiography in patients with atrial fibrillation. Chest 2001;119:144 – 149.
ischemic events in patients with known or suspected CAD undergoing treadmill exercise testing. Methods This was a retrospective analysis of a prospectively collected database. From March 1995 to March 2008, we evaluated 17,100 consecutive patients with known or suspected CAD aged ⱖ50 years who were referred for first treadmill stress testing at our institution. Of them, 11,911 underwent exercise electrocardiography and 5,189 underwent exercise echocardiography. Demographic, clinical, and stress test data were entered in a dedicated database at the time of the tests. All patients gave informed consent before testing, and the study was approved by our local research ethics committee. Blood pressure, heart rate, and a 12-lead electrocardiogram were obtained at baseline and at each stage of the exercise protocol. The electrocardiogram was considered interpretable in the absence of left bundle branch block, paced rhythm, preexcitation, left ventricular hypertrophy, repolarization abnormalities, or treatment with digoxin. Patients underwent a treadmill exercise test until they reached an end point, including physical exhaustion, severe angina, exercise-induced ST-segment deviation ⬎2 mm, significant www.AJConline.org
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Table 1 Baseline characteristics of the 17,100 patients Variable
Men Age (years) Diabetes mellitus Hypertension Hypercholesterolemia Smokers Family history of coronary artery disease Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary bypass Left bundle branch block Typical angina pectoris  blockers Calcium channel blockers Digoxin Nitrates Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers Diuretics Left ventricular ejection fraction at rest*
All Patients (n ⫽ 17,100)
10,101 (59.1%) 64.3 ⫾ 8.2 2,675 (15.6%) 8,442 (49.4%) 7,619 (44.6%) 3,694 (21.6%) 2,032 (11.9%) 2,963 (17.3%) 1,550 (9.1%) 508 (3%) 600 (3.5) 1,015 (5.9%) 2,098 (12.3%) 2,555 (14.9%) 387 (2.3%) 3,983 (23.3%) 4,169 (24.4%) 1,259 (7.4%) 56.3 ⫾ 10.0
AF
p Value
No (n ⫽ 16,481)
Yes (n ⫽ 619)
9,713 (58.9%) 64.1 ⫾ 8.1 2,585 (15.7) 8,138 (49.4%) 7,430 (45.1%) 3,614 (21.9%) 1,975 (12%) 2,871 (17.4%) 1,506 (9.1%) 484 (2.9%) 574 (3.5%) 983 (6%) 1,998 (12.1%) 2,447 (14.8%) 141 (0.9%) 3,792 (23%) 3,944 (23.9%) 1,085 (6.6%) 56.6 ⫾ 9.7
388 (62.7%) 69.2 ⫾ 7.6 90 (14.5%) 304 (49.1%) 189 (30.5%) 80 (12.9%) 57 (9.2%) 92 (14.9%) 44 (7.1%) 24 (3.9%) 26 (4.2%) 32 (5.2%) 100 (16.2%) 108 (17.4%) 246 (39.7%) 191 (30.9%) 225 (36.3%) 174 (28.1%) 52.8 ⫾ 12.0
0.06 ⬍0.001 0.44 0.90 ⬍0.001 ⬍0.001 0.04 0.10 0.08 0.18 0.34 0.41 0.003 0.07 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
Data are expressed as number (percentage) or as mean ⫾ SD. * Available in the subset of 5,189 patients who underwent exercise echocardiography.
arrhythmias, severe hypertension (systolic blood pressure ⬎240 mm Hg or diastolic blood pressure ⬎110 mm Hg), or severe hypotensive response (decrease ⱖ20 mm Hg in systolic blood pressure from baseline value). Exercise protocols included the Bruce (95.6%), modified Bruce (2%), Naughton (1.1%), and other (1.4%) protocols. In patients with interpretable rest electrocardiograms, positive exercise electrocardiographic results were defined as the development of ST-segment deviation ⱖ1 mm that was horizontal or sloping away from the isoelectric line 80 ms after the J point. In the subset of patients who underwent treadmill exercise echocardiography, imaging was performed at rest, at peak exercise, and immediately after exercise, as previously described.9,10 Peak exercise images were acquired with the patient still exercising, when signs of exhaustion were present or an end point was achieved. The transducer was firmly placed on the apical and parasternal areas, and pressure was applied to the patient’s back with the left hand to decrease the relative movement between the transducer and the patient’s body. Peak and postexercise images were obtained using a continuous imaging acquisition system. The best quality images corresponding to each view were selected for comparison with those acquired at rest. Positive exercise echocardiographic results were defined as the appearance of new or worsening exercise-induced wall motion abnormalities, except worsening from akinesia to dyskinesia and isolated hypokinesia of the inferobasal segment. Coronary angiography was performed at the discretion of the referring physician. A significant coronary stenosis was defined as a ⱖ50% luminal stenosis of the left main coronary artery or a ⱖ70% stenosis of any other major epicardial coronary artery. Coronary angiographic results ⬍90 days after the tests were recorded.
Follow-up data were obtained by review of hospital databases, medical records, death certificates, and telephone interviews. End points were all-cause mortality, nonfatal myocardial infarction, and coronary revascularization procedures. We did not evaluate cardiac mortality, because the ascertainment of the cause of death may be liable to bias and misclassification.11 Categorical variables were compared between groups using the chi-square test and are reported as percentages. Continuous variables were assessed using the unpaired Student’s t test or the Mann-Whitney U test as appropriate and are reported as mean ⫾ SD. Survival free of the end point of interest was estimated using the Kaplan-Meier method, and survival curves were compared using the log-rank test. Multivariate logistic regression analyses were performed to determine the adjusted odds ratios for the association of AF with myocardial ischemia on exercise electrocardiography and exercise echocardiography, as well as with the presence of angiographically proved CAD. Adjusted hazard ratios for the association of AF with the end points were estimated using Cox proportional-hazard models. Whenever appropriate, multivariate analyses were adjusted by age, gender, diabetes mellitus, hypertension, hypercholesterolemia, smoking habit, family history of CAD, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass grafting, typical angina, left bundle branch block,  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, nitrates, calcium channel blockers, digoxin, diuretics, exercise-induced chest pain, exercise electrocardiographic results, METs, peak systolic blood pressure, and percentage of maximum age-predicted heart rate. Multivariate analyses performed in the subgroup of patients who underwent exercise echocardiography were
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Table 2 Exercise data obtained during the tests Variable
All Patients (n ⫽ 17,100)
Peak systolic blood pressure (mm Hg) Peak heart rate (beats/min) % of age-predicted maximum heart rate Peak rate–pressure product (⫻103 mm Hg · beats/min) Exercise-induced chest pain METs
175.9 ⫾ 31.1 143.3 ⫾ 21.1 92.0 ⫾ 12.8 25.3 ⫾ 6.2 2,133 (12.5%) 8.8 ⫾ 2.8
AF
p Value
No (n ⫽ 16,481)
Yes (n ⫽ 619)
176.6 ⫾ 30.9 142.9 ⫾ 20.5 91.5 ⫾ 12.3 25.4 ⫾ 6.2 2,086 (12.7%) 8.9 ⫾ 2.9
156.8 ⫾ 30.6 156.9 ⫾ 28.8 103.9 ⫾ 18.7 24.7 ⫾ 6.9 47 (7.6%) 6.7 ⫾ 2.8
⬍0.001 ⬍0.001 ⬍0.001 0.03 ⬍0.001 ⬍0.001
Data are expressed as mean ⫾ SD or as number (percentage). Table 3 Association of atrial fibrillation with ischemic electrocardiographic changes, ischemia on exercise echocardiography, and angiographically proved coronary artery disease Variable Positive exercise electrocardiographic results Positive exercise echocardiographic results Angiographically proved CAD
Adjusted Odds Ratio (95% CI)
p Value
0.51 (0.34–0.76)
0.001
0.62 (0.44–0.87)
0.006
0.66 (0.33–1.35)
0.26
also adjusted by rest left ventricular ejection fraction and exercise-induced wall motion abnormalities. A p value ⬍0.05 was considered significant. Statistical analyses were carried out using SPSS version 15.0 (SPSS, Inc., Chicago, Illinois). Results Of the 17,100 patients, 619 (3.6%) presented with AF at the time of the exercise stress tests. Baseline characteristics of the 17,100 patients are listed in Table 1, and exercise data are listed in Table 2. A total of 15,324 patients had interpretable rest electrocardiograms. Of them, 2,516 patients (16.4%) developed significant exercise-induced ST-segment abnormalities, and the latter occurred less frequently in patients with AF (12.0% vs 16.5% in patients without AF, p ⫽ 0.028). In contrast, among the subgroup of 5,189 patients who underwent exercise echocardiography, 1,778 patients (34.3%) developed new or worsening wall motion abnormalities during exercise, which also were less likely in patients with AF (22.2% vs 35.1% in patients without AF, p ⬍0.001). These associations remained significant after adjustment for other potential confounders (Table 3). Overall, 1,668 patients underwent coronary angiography ⬍90 days after the treadmill tests. Of them, 1,237 (77.7%) showed significant coronary stenoses. The likelihood of angiographically proved CAD in patients with AF who underwent coronary angiography (52.0%) was significantly less than that of patients without AF (77.7%) (p ⬍0.001). However, these results did not remain significant after covariate adjustment (Table 3). During a mean follow-up period of 6.5 ⫾ 3.9 years, 2,364 patients died, 1,311 had nonfatal myocardial infarctions, 1,615 underwent percutaneous coronary intervention,
Figure 1. All-cause mortality curves in patients with and without AF.
and 922 underwent coronary artery bypass surgery. The 10-year mortality rate was 43% in patients with AF compared to 19% in patients without AF (p ⬍0.001; Figure 1). Figure 2 shows the relation of AF with all-cause mortality stratified according to exercise electrocardiographic and exercise echocardiographic results. In multivariate analysis, AF was an independent predictor of all-cause mortality risk, but it did not remain significantly associated with nonfatal myocardial infarction or coronary revascularization (Table 4). The association of AF with mortality remained consistent even when the subgroup of patients who underwent exercise echocardiography was selectively evaluated and rest left ventricular ejection fraction and exercise-induced wall motion abnormalities were included in the multivariate analysis (adjusted hazard ratio 1.54, 95% confidence interval [CI] 1.19 to 1.98, p ⬍0.001). In the subset of patients without histories of CAD, those with AF and interpretable rest electrocardiograms had a lower likelihood of ischemic electrocardiographic changes during the tests (adjusted odds ratio 0.53, 95% CI 0.33 to 0.84, p ⫽ 0.007); in addition, those patients who underwent exercise echocardiography who had AF also had a lower likelihood of echocardiographic myocardial ischemia (adjusted odds ratio 0.57, 95% CI 0.37 to 0.89, p ⫽ 0.01). The
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Figure 2. All-cause mortality curves in patients with and without AF according to (A) exercise electrocardiographic (ExECG) and (B) exercise echocardiographic (ExEcho) results. Table 4 Prognostic value of atrial fibrillation in patients with known or suspected coronary artery disease Variable All-cause mortality Nonfatal myocardial infarction Coronary revascularization
Adjusted Hazard Ratio (95% CI)
p Value
1.45 (1.20–1.76) 0.77 (0.53–1.11) 1.05 (0.79–1.39)
⬍0.001 0.16 0.84
10-year mortality rate in patients without history of CAD who had AF was higher than that of patients without AF (39.9% vs 16.4%, p ⬍0.001). As in the overall population, AF remained an independent predictor of mortality in this subgroup of patients (adjusted hazard ratio 1.55, 95% CI 1.23 to 1.96, p ⬍0.001). Discussion This study is the first to assess the association of AF with myocardial ischemia, CAD, and outcomes in patients with known or suspected CAD referred for exercise stress testing. Despite being associated with an apparently lower likelihood of myocardial ischemia, as assessed by exercise electrocardiography and exercise echocardiography, AF was an independent predictor of all-cause mortality in these patients. However, we did not observe a significant, independent association with nonfatal coronary events. Whether the likelihood of obstructive CAD or future coronary events is increased in patients with AF remains controversial.7,12 Some studies have reported either a low prevalence of AF in patients with CAD5,6,13 or a lack of association between AF and CAD.14 Others, however, have suggested a link between these 2 entities. In patients without histories of CAD, Nucifora et al15 found a higher prevalence of obstructive CAD, as assessed by multislice computed tomography, in those patients with AF. In the same line, Pierre-Louis et al16 observed that patients with diabetes mellitus who had AF had a higher prevalence of significant CAD than those in sinus rhythm. In contrast, Marte et al8 found that AF was associated with a lower prevalence of angiographically determined CAD, suggesting that AF may produce symptoms leading to referral for coronary angiography in the absence of significant CAD. In this latter study, however, patients with AF were paradoxically at increased
risk for future coronary events. Miyasaka et al17 also found a high incidence of coronary events in patients with AF without histories of CAD. In our study, the apparent association between AF and a lower likelihood of angiographically proved CAD in the subgroup of patients referred for coronary angiography did not remain significant after multivariate adjustment. In addition, we failed to find a significant association between AF and future nonfatal coronary events. Notwithstanding these controversies, previous reports agree that the combination of AF and CAD portends a higher mortality risk.6,8 Our study complements and expands on these observations by demonstrating a significant association of AF with all-cause mortality in patients with known or suspected CAD referred for exercise stress testing. This study had the limitations inherent in its retrospective and observational design. Only a small proportion of patients in our cohort underwent coronary angiography ⬍90 days after the tests; thus, our results regarding the association of AF with coronary angiographic findings may be affected by referral bias. In addition, the increased chronotropic response to exercise in patients with AF18 and the beat-to-beat variations in the length of cardiac cycles might affect the accuracy of noninvasive stress tests.19 Moreover, the diagnostic and prognostic values of exercise echocardiography in patients with AF have not yet been specifically evaluated. Thus, further studies addressing this issue are warranted. 1. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469 – 473. 2. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285:2370 –2375. 3. Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol 2001;37:371–378. 4. Veloso HH, Diniz MC. Are physicians recommending coronary angiographies more than necessary in atrial fibrillation? Int J Cardiol 2000;76:85– 88. 5. Haddad AH, Prchkov VK, Dean DC. Chronic atrial fibrillation and coronary artery disease. J Electrocardiol 1978;11:67– 69. 6. Cameron A, Schwartz MJ, Kronmal RA, Kosinski AS. Prevalence and significance of atrial fibrillation in coronary artery disease (CASS registry). Am J Cardiol 1988;61:714 –717.
Coronary Artery Disease/Atrial Fibrillation, CAD, and Outcomes 7. Wheeldon N. Coronary heart disease and atrial fibrillation. Studies have not shown a causal relation. BMJ 1996;312:641– 642. 8. Marte T, Saely CH, Schmid F, Koch L, Drexel H. Effectiveness of atrial fibrillation as an independent predictor of death and coronary events in patients having coronary angiography. Am J Cardiol 2009; 103:36 – 40. 9. Bouzas-Mosquera A, Peteiro J, Álvarez-Garcia N, Broullon FJ, Mosquera VX, Garcia-Bueno L, Ferro L, Castro-Beiras A. Prediction of mortality and major cardiac events by exercise echocardiography in patients with normal exercise electrocardiographic testing. J Am Coll Cardiol 2009;53:1981–1990. 10. Peteiro J, Bouzas-Mosquera A, Broullon FJ, Garcia-Campos A, Pazos P, Castro-Beiras A. Prognostic value of peak and post-exercise treadmill exercise echocardiography in patients with known or suspected coronary artery disease. Eur Heart J 2010;31:187–195. 11. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death in clinical research: time for a reassessment? J Am Coll Cardiol 1999; 34:618 – 620. 12. Lokshyn S, Mewis C, Kuhlkamp V. Atrial fibrillation in coronary artery disease. Int J Cardiol 2000;72:133–136. 13. Galrinho A, Gomes JA, Antunes E, Catarino C, da Silva N, Ferreira R, Quininha J, Rato JA. Atrial fibrillation and coronary disease [article in Portuguese]. Rev Port Cardiol 1993;12:1037–1940.
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14. Onundarson PT, Thorgeirsson G, Jonmundsson E, Sigfusson N, Hardarson T. Chronic atrial fibrillation— epidemiologic features and 14 year follow-up: a case control study. Eur Heart J 1987;8:521–527. 15. Nucifora G, Schuijf JD, Tops LF, van Werkhoven JM, Kajander S, Jukema JW, Schreur JH, Heijenbrok MW, Trines SA, Gaemperli O, Turta O, Kaufmann PA, Knuuti J, Schalij MJ, Bax JJ. Prevalence of coronary artery disease assessed by multislice computed tomography coronary angiography in patients with paroxysmal or persistent atrial fibrillation. Circ Cardiovasc Imaging 2009;2:100 –106. 16. Pierre-Louis B, Aronow WS, Palaniswamy C, Singh T, Weiss MB, Kalapatapu K, Pucillo AL, Monsen CE. Obstructive coronary artery disease in high-risk diabetic patients with and without atrial fibrillation. Coron Artery Dis 2009;20:91–93. 17. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Seward JB, Iwasaka T, Tsang TS. Coronary ischemic events after first atrial fibrillation: risk and survival. Am J Med 2007;120:357–363. 18. Hilliard AA, Miller TD, Hodge DO, Gibbons RJ. Heart rate control in patients with atrial fibrillation referred for exercise testing. Am J Cardiol 2008;102:704 –708. 19. Poldermans D, Bax JJ, Elhendy A, Sozzi F, Boersma E, Thomson IR, Jordaens LJ. Long-term prognostic value of dobutamine stress echocardiography in patients with atrial fibrillation. Chest 2001;119:144 – 149.