ORIGINAL CONTRIBUTION. Relationship Between Chronic Atrial Fibrillation and Worse Outcomes in Stroke Patients After Intravenous Thrombolysis

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1 ORIGINAL CONTRIBUTION Relationship Between Chronic Atrial Fibrillation and Worse Outcomes in Stroke After Intravenous Thrombolysis Raymond C. S. Seet, MD; Yi Zhang, MD; Eelco F. Wijdicks, MD, PhD; Alejandro A. Rabinstein, MD Background: It is unclear whether stroke patients with atrial fibrillation (AF) are prone to adverse outcomes following treatment with intravenous recombinant tissue plasminogen activator, and whether the burden of AF affects these outcomes. Objective: To investigate the contribution of AF (whether it be a first-detected episode of AF or chronic AF) to stroke outcomes in patients treated with intravenous recombinant tissue plasminogen activator. Design: Retrospective study. Setting: Academic hospital. : Consecutive patients with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator within 3 hours from symptom onset were included. Vascular risk factors, stroke characteristics, and outcome measures were compared between patients with and without AF. Main Outcome Measures: Symptomatic intracranial hemorrhage and poor functional recovery (modified Rankin Scale score of 2). Results: Of the 214 patients who were studied (mean [SD] age, 74 [14] years, with 50% of patients being men), 21 had a first-detected episode of AF, and 55 had chronic AF. The incidence of symptomatic intracranial hemorrhage was significantly higher in patients with chronic AF than in patients without AF (16% vs 5%), and the incidence of poor functional recovery was significantly higher in patients with chronic AF than in patients without AF (62% vs 44%). The increase in risk of symptomatic intracranial hemorrhage (but not in poor functional recovery) among patients with chronic AF remained significant after adjusting for age and baseline National Institutes of Health Stroke Scale score (odds ratio, 2.95 [95% CI, ]). with chronic AF who developed a symptomatic intracranial hemorrhage had a longer duration of AF than those who did not (59 vs 23 months), and patients with chronic AF who had a poor functional recovery had a longer duration of AF than those who did not (36 vs 16 months) (P.05). By contrast, there were no differences in outcomes between patients with a first-detected episode of AF and those without AF, and between patients with paroxysmal AF and those with persistent or permanent AF. Conclusions: with chronic AF have worse stroke outcomes than do patients without AF, and the risk for worse outcomes was greater in patients with a longer duration of AF. Arch Neurol. 2011;68(11): Author Affiliations: Department of Neurology, Mayo Clinic, Rochester, Minnesota (Drs Seet, Zhang, Wijdicks, and Rabinstein); and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Dr Seet). ATRIAL FIBRILLATION (AF) confers increased risks of stroke and death. 1,2 Population- and hospital-based studies indicate that 20% to 25% of all strokes are caused by AF, and AFrelated strokes are more severe than strokes of other causes. 3,4 Pooled analysis of the third European Cooperative Acute Stroke Study, the ATLANTIS (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke) study, the National Institute of Neurological Disorders and Stroke trial, the Echoplanar Imaging Thrombolytic Evaluation Trial, 5 the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Registry database, 6 and the Get With the Guidelines Stroke database 7 indicate that 1 in 5 stroke patients treated with intravenous recombinant tissue plasminogen activator (rtpa) have concomitant AF. Several studies 8-10 have implicated AF as a risk predictor for adverse stroke outcomes, whereas another study 11 did not observe differences in stroke outcomes between patients with and without AF. Among patients with acute myocardial infarction, those with chronic AF had higher inhospital mortality than did patients with a first-detected episode of AF. 12 It is unclear whether patients with AF (whether it be a first-detected episode of AF or chronic AF) would respond differently to rtpa treatment and whether the burden of AF has any consequence on stroke outcomes. We performed a retrospective analysis to investigate the effect of AF on stroke outcomes among rtpa-treated patients. 1454

2 METHODS Between April 2006 and September 2010, consecutive patients with acute ischemic stroke who received intravenous rtpa within 3 hours from symptom onset at St Marys Hospital, operated by the Mayo Clinic in Rochester, Minnesota, were included in our study. who underwent primary or adjunctive endovascular treatments owing to contraindication to or following intravenous rtpa were excluded. All patients eligible for intravenous rtpa were treated using a standard protocol adopted from the American Heart Association/American Stroke Association guidelines. 13 Information on vascular risk factors, stroke severity, and baseline hemodynamic and laboratory indices was collected. Atrial fibrillation was diagnosed by use of a 12-lead electrocardiogram or by 24-hour continuous electrocardiographic monitoring, and patients were classified as having a first-detected episode of AF or as having chronic AF. Episodes of AF that terminated spontaneously were considered paroxysmal, and those that were sustained beyond 7 days were considered persistent. 1,2 The category of persistent AF also included patients with permanent AF, in whom cardioversion had failed or had not been attempted. 1,2 The duration of AF was considered as the time between the physician s diagnosis and stroke onset. Computed tomographic scans of the brain were performed before treatment with intravenous rtpa began and were repeated 24 hours later or whenever clinically indicated for patients with worsening stroke symptoms. Additional diagnostic tests, which included ultrasonography, magnetic resonance angiography, computed tomographic angiography, and echocardiography, were performed to identify potential mechanisms of cerebral infarction, and on the basis of the results, etiologic subgroups were determined using the Trial of ORG in Acute Stroke Treatment criteria. 14 The presence and severity of intracranial hemorrhage (ICH) were determined and classified, respectively, according to the criteria of the European Cooperative Acute Stroke Study. 15 Symptomatic ICH was defined by hemorrhagic transformation that was associated with at least a 4-point increment in the National Institutes of Health Stroke Scale score. Functional recovery was determined 3 months after stroke onset using the modified Rankin Scale. Poor outcome was considered for those whose modified Rankin Scale score was greater than The study protocol was approved by the Mayo Clinic institutional review board. Statistical analyses were performed using SPSS software version 16.0 (SPSS Inc, Chicago, Illinois). Data are presented as means and standard deviations for continuous measures and as counts and percentages for categorical variables. Differences between patients with and without AF were compared using the unpaired t and Wilcoxon rank sum tests for continuous measures and the 2 and Fisher exact tests for categorical variables. Unadjusted and adjusted odds ratios (95% CIs) were derived using logistic regression analyses. Statistical significance was considered when P.05. RESULTS Of 249 patients who received rtpa treatment, 35 were excluded from our study because they underwent an endovascular procedure. The remaining 214 patients formed the primary study cohort; their characteristics are summarized in Table 1. Seventy-six patients had chronic AF or a first-detected episode of AF; of these 76 patients, 44 were diagnosed with paroxysmal AF, and 32 with persistent AF. Valvular heart disease was found in Table 1. Comparison Between With and Without Atrial Fibrillation Treated With Intravenous Recombinant Tissue Plasminogen Activator Characteristic With AF (n=76) Without AF (n=138) P Value Age, mean (SD), y 78.9 (9.9) 71.5 (14.8).001 Male, No. (%) 32 (42) 74 (54).11 Medical history, No. (%) Hypertension 60 (79) 104 (75).55 Diabetes mellitus 8 (11) 20 (14).41 Hyperlipidemia 38 (50) 71 (51).84 Coronary artery disease 30 (39) 49 (36).57 Prior stroke or TIA 14 (18) 33 (24).35 Currently smoking 6 (8) 23 (16).21 Medications, No. (%) Antidiabetic drugs 5 (7) 12 (9).58 Lipid-lowering drugs 30 (40) 59 (43).64 Warfarin sodium 12 (16) 2 (1).001 Antiplatelets 45 (59) 75 (54).49 Stroke characteristics Baseline NIHSS score, 13 (10-16) 12 (8-16).30 median (IQR) Onset-to-treatment time, (31.2) (25.1).55 mean (SD), min Cardioembolic stroke, 74 (97) 36 (26).004 No. (%) Blood pressure, mean (SD), mm Hg Systolic (26.8) (22.8).27 Diastolic 79.7 (21.9) 79.3 (15.8).87 Heart rate, mean (SD), 80.8 (22.5) 74.7 (14.2).02 beats/min Laboratory parameters, mean (SD) Hemoglobin, g/dl 1.31 (0.16) 1.34 (0.17).33 Hematocrit, % (4.50) (4.70).45 White blood cell 9.9 (5.6) 8.9 (4.1).19 count, /µl Platelet count, (99.0) (62.7) /µl Glucose, mg/dl (24.9) (43.5).59 INR (range) 1.0 ( ) 1.0 ( ).10 APTT, s (5.73) (6.24).43 Outcome measures, No. (%) Symptomatic ICH 10 (13) 7 (5).04 Poor functional recovery a 44 (58) 61 (44).06 Abbreviations: AF, atrial fibrillation; APTT, activated partial thromboplastin time; ICH, intracranial hemorrhage; INR, international normalized ratio; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack. SI conversion factors: To convert hemoglobin to grams per liter, multiply by 10; to convert hematocrit to proportion of 1.0, multiply by 0.01; to convert white blood cell count to 10 9 per liter, multiply by 0.001; to convert platelet count to 10 9 per liter, multiply by 1.0; and to convert glucose to millimoles per liter, multiply by a Modified Rankin Scale score of greater than 2. 4 of the 76 patients with AF (5%) (3 with mitral regurgitation and 1 with mitral stenosis). with AF (both those with a first-detected episode of AF and those with chronic AF) had a higher incidence of symptomatic ICH and a worse 90-day functional recovery compared with those without AF (Table 1 and Figure). The incidence of symptomatic ICH was significantly higher in patients with chronic AF than in patients without AF (16% vs 5%), and the incidence of poor 1455

3 0 1 With Chronic AF (n = 55) With a First-Detected Episode of AF (n = 21) Without AF (n = 138) 0 Modified Rankin Scale Score , % Figure. Distribution of modified Rankin Scale scores: 0 indicates no symptoms at all; 1, no significant disability despite symptoms (patient is able to perform all of his or her usual duties and activities); 2, slight disability (patient is unable to perform all of his or her previous activities but is able to look after his or her own affairs without assistance); 3, moderate disability (patient requires some help but is able to walk without assistance); 4, moderately severe disability (patient is unable to walk without assistance and is unable to attend to his or her own bodily needs without assistance); 5, severe disability (patient is bedridden, incontinent, and requires constant nursing care and attention); and 6, dead. The distributions between study groups were compared by use of the Cochran-Mantel-Haenszel test (patients with chronic atrial fibrillation [AF] vs patients without AF [P=.03]; patients with a first-detected episode of AF vs patients without AF [P=.53]; and patients with chronic AF vs patients with a first-detected episode of AF [P=.09]). functional recovery (modified Rankin Scale score, 2) was significantly higher in patients with chronic AF than in patients without AF (62% vs 44%). with chronic AF were generally older, had used warfarin sodium more frequency in the past, and had an increased heart rate (Table 2). The increased risk of symptomatic ICH (but not poor functional recovery) among patients with chronic AF remained significant after adjustments were made for age and baseline National Institutes of Health Stroke Scale score (odds ratio, 2.95 [95%, CI ]) (Table 3). with chronic AF who developed symptomatic ICH had a longer duration of AF than those who did not (59 vs 23 months), and patients with chronic AF who experienced poor functional recovery had a longer duration of AF than those who did not (36 vs 16 months) (P.05). By contrast, there were no differences in outcomes between patients with a firstdetected episode of AF and patients without AF or between patients with paroxysmal AF and patients with persistent or permanent AF. COMMENT To our knowledge, this is the first study that distinguished stroke patients according to the duration of AF and that evaluated the significance of this distinction with respect to outcomes after rtpa administration. In our study, we observed that patients with AF were found to be more prone to developing adverse stroke outcomes such as symptomatic ICH and poor functional recovery following rtpa treatment. On closer analysis, the increased risks were observed mainly among patients with chronic AF but not among those with a first-detected episode of AF. These data also highlight a high frequency of paroxysmal AF among stroke patients who present within the time window for rtpa treatment. Table 2. Comparison Between With Chronic AF Treated With Intravenous rtpa and Without AF Treated With Intravenous rtpa Characteristic With Chronic AF (n=55) Without AF (n=138) P Value Age, mean (SD), y 78.7 (9.1) 71.5 (14.8).001 Male, No. (%) 24 (44) 74 (54).21 Medical history, No. (%) Hypertension 44 (80) 104 (75).49 Diabetes mellitus 6 (11) 20 (14).51 Hyperlipidemia 26 (47) 71 (51).60 Coronary artery disease 23 (42) 49 (36).41 Prior stroke or TIA 10 (18) 33 (24).39 Currently smoking 4 (4) 23 (16).16 Medications, No. (%) Antidiabetic drugs 5 (9) 12 (9).93 Lipid-lowering drugs 22 (40) 59 (43).73 Warfarin sodium 12 (22) 2 (1).001 Antiplatelets 30 (55) 75 (54).98 Stroke characteristics Baseline NIHSS score, 14 (10-18) 12 (8-16).09 median (IQR) Onset-to-treatment time, (71.6) (25.1).44 mean (SD), min Cardioembolic strokes, 54 (98) 36 (26).41 No. (%) Blood pressure, mean (SD), mm Hg Systolic (28.6) (22.8).36 Diastolic 80.6 (23.3) 79.3 (15.8).66 Heart rate, mean (SD), 81.1 (24.8) 74.7 (14.2).03 beats/min Laboratory parameters Hemoglobin, g/dl 1.31 (0.15) 1.34 (0.17).32 Hematocrit, % 38.5 (4.2) (4.70).41 White blood cell count, /µl 9.8 (5.9) 8.9 (4.1).29 Platelet count, 10 3 /µl 232 (112) (62.7).69 Glucose, mg/dl (22.7) (43.5).77 INR (range) 1.0 ( ) 1.0 ( ).07 APTT, s (6.41) (6.24).41 Outcome measures, No. (%) Symptomatic ICH 9 (16) 7 (5).010 Poor functional recovery a 34 (62) 61 (44).03 Abbreviations: AF, atrial fibrillation; APTT, activated partial thromboplastin time; ICH, intracranial hemorrhage; INR, international normalized ratio; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale score; rtpa, recombinant tissue plasminogen activator; TIA, transient ischemic attack. SI conversion factors: To convert hemoglobin to grams per liter, multiply by 10; to convert hematocrit to proportion of 1.0, multiply by 0.01; to convert white blood cell count to 10 9 per liter, multiply by 0.001; to convert platelet count to 10 9 per liter, multiply by 1.0; and to convert glucose to millimoles per liter, multiply by a Modified Rankin Scale score of greater than 2. Our findings are consistent with those of previous studies 8-10 that observed a significant increase (or trend) in the risk of symptomatic ICH or poor functional recovery among patients with AF treated with rtpa. One study 8 reported that patients with AF were 3 times more likely than patients without AF to have poor functional recovery at 90 days. Two other studies 9,10 found significant associations between AF and worse 90-day functional recovery on univariate, but not on multivariable, analyses. These findings, however, appear to conflict with those of another study 11 (which enrolled fewer and younger patients) that 1456

4 Table 3. Data on Main Outcome Measures of 214 With Stroke Outcome Measure With AF vs Without AF Adjusted Odds Ratio (95% CI) a With a First-Detected Episode of AF vs Without AF With Chronic AF vs Without AF Symptomatic ICH 2.55 ( ) 1.18 ( ) 2.95 ( ) b Poor functional recovery 1.25 ( ) 1.05 ( ) 1.45 ( ) Abbreviations: AF, atrial fibrillation; ICH, intracranial hemorrhage; NIHSS, National Institutes of Health Stroke Scale. a Adjusted for age and baseline NIHSS score using multivariable logistic regression analysis. b Denotes P.05, after adjusting for age and baseline NIHSS score. reported the lack of such differences between patients with and without AF. Similar to studies 12,17,18 of patients with acute myocardial infarction, the patients with AF included in our study were generally older, were more frequently treated with warfarin (the international normalized ratio was subtherapeutic in all cases because the therapeutic international normalized ratio would have contraindicated the administration of intravenous thrombolysis), and had a faster heart rate on admission. Data from several studies 19,20 suggest that clots associated with AF are more resistant to dissolution with rtpa. In the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi MERCI trials, 19 close to 50% of patients whose rtpa treatment failed and who subsequently underwent intracranial mechanical thrombectomy had concomitant AF, whereas in a magnetic resonance angiography study, 20 the presence of AF was identified as an independent predictor of failure to recanalize with intravenous rtpa treatment. In our study, worse stroke outcomes were observed in patients with chronic AF, and the risk of adverse outcomes appears to increase with increasing duration of AF. It is not known whether the presence of AF reflects an adverse marker of global cardiovascular risks or whether the duration of AF is a cumulative surrogate of this burden. In the context of ischemic stroke, the chronicity of AF may affect the characteristics of the culprit clots and their resistance to rtpa treatment. Clots that are formed over a longer interval within the atrium or atrial appendage and that are characteristically larger may be capable of abruptly occluding proximal arteries, causing a larger area of cerebral ischemia and infarct size. It is unclear whether red thrombi, derived from intracardiac thrombi or venous thrombi traversing the heart, 21 would respond differently to rtpa treatment. Pathologic studies 21,22 have consistently observed the notable absence of calcific components (a marker of chronicity) in retrieved thromboemboli and cardiac samples. Paroxysmal AF, a self-terminating recurrent form of cardiac arrhythmia that is observed in 25% to 62% of AF cases, may be experienced as a brief single episode of arrhythmia or as a cluster of abnormal rhythms of variable duration, sometimes evolving into a more persistent and permanent form. 1,2 Despite carrying the same stroke risk as permanent or persistent AF, the burden of paroxysmal AF among rtpa-treated patients is underrecognized. 23 In our study, close to 60% of patients with AF who presented within the therapeutic window for intravenous rtpa treatment had paroxysmal AF. With wider use of prolonged cardiac monitoring, the burden of paroxysmal AF contributing to the mechanisms underlying stroke is expected to increase. 24 In one study 25 that incorporated 30-day cardiac event monitors, close to onefifth of patients with cryptogenic stroke were found to have paroxysmal AF. Because of the small sample size and retrospective design of our study, we were not able to perform additional subgroup analyses to identify high-risk patients and determine the proportion of patients with a first-detected episode of AF who may have asymptomatic occult AF paroxysms but who might have been inappropriately classified as not having AF. The fewer number of patients with symptomatic ICH may also subject our findings to type 2 errors. Because angiography was not performed for all patients, we were unable to accurately assess the extent of thrombus burden prior to thrombolysis and address the question of whether the increased risks for adverse outcomes are related to greater thrombus burden in patients with chronic AF. These data suggest that patients with chronic AF are vulnerable to adverse stroke outcomes and that the risk for worse outcomes was greater in patients with a longer duration of AF. This information is useful to identify stroke patients at higher risk for adverse stroke outcomes following rtpa treatment who may benefit from closer blood pressure control and monitoring and, perhaps, early endovascular treatment. Accepted for Publication: May 5, Correspondence: Raymond C. S. Seet, MD, Department of Neurology, Mayo Clinic, W8B, 200 First St SW, Rochester, MN (raymond_seet@nus.edu.sg). Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Seet and Rabinstein. Acquisition of data: Seet and Zhang. Analysis and interpretation of data: Seet, Wijdicks, and Rabinstein. Drafting of the manuscript: Seet and Zhang. Critical revision of the manuscript for important intellectual content: Seet, Wijdicks, and Rabinstein. Statistical analysis: Seet. Administrative, technical, and material support: Seet and Zhang. Study supervision: Wijdicks and Rabinstein. Financial Disclosure: None reported. REFERENCES 1. Fuster V, Rydén LE, Cannom DS, et al; American College of Cardiology/ American Heart Association Task Force on Practice Guidelines; European Soci- 1457

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