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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]).

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]).

Table 1. Comparison Between Patients With and Without Atrial Fibrillation Treated With Intravenous Recombinant Tissue Plasminogen Activator
Table 1. Comparison Between Patients With and Without Atrial Fibrillation Treated With Intravenous Recombinant Tissue Plasminogen Activator
Table 2. Comparison Between Patients With Chronic AF Treated With Intravenous rtPA and Patients Without AF Treated With Intravenous rtPA
Table 2. Comparison Between Patients With Chronic AF Treated With Intravenous rtPA and Patients Without AF Treated With Intravenous rtPA
Table 3. Data on Main Outcome Measures of 214 Patients With Stroke
Table 3. Data on Main Outcome Measures of 214 Patients With Stroke
1.
Fuster V, Rydén LE, Cannom DS,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society.  ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.  Circulation. 2006;114(7):e257-e354PubMedArticle
2.
Camm AJ, Kirchhof P, Lip GY,  et al; European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery.  Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).  Eur Heart J. 2010;31(19):2369-2429PubMedArticle
3.
Miyasaka Y, Barnes ME, Gersh BJ,  et al.  Time trends of ischemic stroke incidence and mortality in patients diagnosed with first atrial fibrillation in 1980 to 2000: report of a community-based study.  Stroke. 2005;36(11):2362-2366PubMedArticle
4.
Asberg S, Henriksson KM, Farahmand B,  et al.  Ischemic stroke and secondary prevention in clinical practice: a cohort study of 14,529 patients in the Swedish Stroke Register.  Stroke. 2010;41(7):1338-1342PubMedArticle
5.
Lees KR, Bluhmki E, von Kummer R,  et al; ECASS, ATLANTIS, NINDS and EPITHET rt-PA Study Group.  Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.  Lancet. 2010;375(9727):1695-1703PubMedArticle
6.
Wahlgren N, Ahmed N, Dávalos A,  et al; SITS investigators.  Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study.  Lancet. 2008;372(9646):1303-1309PubMedArticle
7.
Saver JL, Smith EE, Fonarow GC,  et al; GWTG-Stroke Steering Committee and Investigators.  The “golden hour” and acute brain ischemia: presenting features and lytic therapy in >30,000 patients arriving within 60 minutes of stroke onset.  Stroke. 2010;41(7):1431-1439PubMedArticle
8.
Kimura K, Iguchi Y, Shibazaki K, Iwanaga T, Yamashita S, Aoki J. IV t-PA therapy in acute stroke patients with atrial fibrillation.  J Neurol Sci. 2009;276(1-2):6-8PubMedArticle
9.
Tu HT, Campbell BC, Christensen S,  et al; Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) Investigators.  Pathophysiological determinants of worse stroke outcome in atrial fibrillation.  Cerebrovasc Dis. 2010;30(4):389-395PubMedArticle
10.
Sanák D, Herzig R, Král M,  et al.  Is atrial fibrillation associated with poor outcome after thrombolysis?  J Neurol. 2010;257(6):999-1003PubMedArticle
11.
Zhang JB, Ding ZY, Yang Y,  et al.  Thrombolysis with alteplase for acute ischemic stroke patients with atrial fibrillation.  Neurol Res. 2010;32(4):353-358PubMedArticle
12.
Maagh P, Butz T, Wickenbrock I,  et al.  New-onset versus chronic atrial fibrillation in acute myocardial infarction: differences in short- and long-term follow-up.  Clin Res Cardiol. 2011;100(2):167-175PubMedArticle
13.
Adams HP Jr, del Zoppo G, Alberts MJ,  et al; American Heart Association; American Stroke Association Stroke Council; Clinical Cardiology Council; Cardiovascular Radiology and Intervention Council; Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups.  Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.  Stroke. 2007;38(5):1655-1711PubMedArticle
14.
Madden KP, Karanjia PN, Adams HP Jr, Clarke WR. Accuracy of initial stroke subtype diagnosis in the TOAST study. Trial of ORG 10172 in Acute Stroke Treatment.  Neurology. 1995;45(11):1975-1979PubMedArticle
15.
Hacke W, Kaste M, Fieschi C,  et al; The European Cooperative Acute Stroke Study (ECASS).  Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke.  JAMA. 1995;274(13):1017-1025PubMedArticle
16.
Bonita R, Beaglehole R. Recovery of motor function after stroke.  Stroke. 1988;19(12):1497-1500PubMedArticle
17.
Rathore SS, Berger AK, Weinfurt KP,  et al.  Acute myocardial infarction complicated by atrial fibrillation in the elderly: prevalence and outcomes.  Circulation. 2000;101(9):969-974PubMed
18.
Kinjo K, Sato H, Sato H,  et al; Osaka Acute Coronary Insufficiency Study (OACIS) Group.  Prognostic significance of atrial fibrillation/atrial flutter in patients with acute myocardial infarction treated with percutaneous coronary intervention.  Am J Cardiol. 2003;92(10):1150-1154PubMedArticle
19.
Shi ZS, Loh Y, Walker G, Duckwiler GR.MERCI and Multi MERCI Investigators.  Endovascular thrombectomy for acute ischemic stroke in failed intravenous tissue plasminogen activator versus non-intravenous tissue plasminogen activator patients: revascularization and outcomes stratified by the site of arterial occlusions.  Stroke. 2010;41(6):1185-1192PubMedArticle
20.
Kimura K, Iguchi Y, Yamashita S, Shibazaki K, Kobayashi K, Inoue T. Atrial fibrillation as an independent predictor for no early recanalization after IV-t-PA in acute ischemic stroke.  J Neurol Sci. 2008;267(1-2):57-61PubMedArticle
21.
Ogata J, Yutani C, Otsubo R,  et al.  Heart and vessel pathology underlying brain infarction in 142 stroke patients.  Ann Neurol. 2008;63(6):770-781PubMedArticle
22.
Marder VJ, Chute DJ, Starkman S,  et al.  Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke.  Stroke. 2006;37(8):2086-2093PubMedArticle
23.
Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation.  Eur Heart J. 2010;31(8):967-975PubMedArticle
24.
Seet RC, Friedman PA, Rabinstein AA. Prolonged rhythm monitoring for the detection of occult paroxysmal atrial fibrillation in ischemic stroke of unknown cause.  Circulation. 2011;124(4):477-486PubMedArticle
25.
Elijovich L, Josephson SA, Fung GL, Smith WS. Intermittent atrial fibrillation may account for a large proportion of otherwise cryptogenic stroke: a study of 30-day cardiac event monitors.  J Stroke Cerebrovasc Dis. 2009;18(3):185-189PubMedArticle
Original Contributions
Nov 2011

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

Author Affiliations

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).

Arch Neurol. 2011;68(11):1454-1458. doi:10.1001/archneurol.2011.248
Abstract

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.

Patients 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, 1.12-9.30]). Patients 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 Patients 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.

A trial 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 AF-related 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 database7 indicate that 1 in 5 stroke patients treated with intravenous recombinant tissue plasminogen activator (rtPA) have concomitant AF. Several studies810 have implicated AF as a risk predictor for adverse stroke outcomes, whereas another study11 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 in-hospital 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.

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. Patients 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 10172 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 2.16 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 χ2 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 4 of the 76 patients with AF (5%) (3 with mitral regurgitation and 1 with mitral stenosis).

Patients 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 functional recovery (modified Rankin Scale score, >2) was significantly higher in patients with chronic AF than in patients without AF (62% vs 44%). Patients 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 1.12-9.30]) (Table 3). Patients 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 first-detected 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.

Our findings are consistent with those of previous studies810 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 study8 reported that patients with AF were 3 times more likely than patients without AF to have poor functional recovery at 90 days. Two other studies9,10 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 study11 (which enrolled fewer and younger patients) that reported the lack of such differences between patients with and without AF. Similar to studies12,17,18 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 studies19,20 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 studies21,22 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 study25 that incorporated 30-day cardiac event monitors, close to one-fifth 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.

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Article Information

Correspondence: Raymond C. S. Seet, MD, Department of Neurology, Mayo Clinic, W8B, 200 First St SW, Rochester, MN 55905 (raymond_seet@nus.edu.sg).

Accepted for Publication: May 5, 2011.

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 Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society.  ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.  Circulation. 2006;114(7):e257-e354PubMedArticle
2.
Camm AJ, Kirchhof P, Lip GY,  et al; European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery.  Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).  Eur Heart J. 2010;31(19):2369-2429PubMedArticle
3.
Miyasaka Y, Barnes ME, Gersh BJ,  et al.  Time trends of ischemic stroke incidence and mortality in patients diagnosed with first atrial fibrillation in 1980 to 2000: report of a community-based study.  Stroke. 2005;36(11):2362-2366PubMedArticle
4.
Asberg S, Henriksson KM, Farahmand B,  et al.  Ischemic stroke and secondary prevention in clinical practice: a cohort study of 14,529 patients in the Swedish Stroke Register.  Stroke. 2010;41(7):1338-1342PubMedArticle
5.
Lees KR, Bluhmki E, von Kummer R,  et al; ECASS, ATLANTIS, NINDS and EPITHET rt-PA Study Group.  Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.  Lancet. 2010;375(9727):1695-1703PubMedArticle
6.
Wahlgren N, Ahmed N, Dávalos A,  et al; SITS investigators.  Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study.  Lancet. 2008;372(9646):1303-1309PubMedArticle
7.
Saver JL, Smith EE, Fonarow GC,  et al; GWTG-Stroke Steering Committee and Investigators.  The “golden hour” and acute brain ischemia: presenting features and lytic therapy in >30,000 patients arriving within 60 minutes of stroke onset.  Stroke. 2010;41(7):1431-1439PubMedArticle
8.
Kimura K, Iguchi Y, Shibazaki K, Iwanaga T, Yamashita S, Aoki J. IV t-PA therapy in acute stroke patients with atrial fibrillation.  J Neurol Sci. 2009;276(1-2):6-8PubMedArticle
9.
Tu HT, Campbell BC, Christensen S,  et al; Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) Investigators.  Pathophysiological determinants of worse stroke outcome in atrial fibrillation.  Cerebrovasc Dis. 2010;30(4):389-395PubMedArticle
10.
Sanák D, Herzig R, Král M,  et al.  Is atrial fibrillation associated with poor outcome after thrombolysis?  J Neurol. 2010;257(6):999-1003PubMedArticle
11.
Zhang JB, Ding ZY, Yang Y,  et al.  Thrombolysis with alteplase for acute ischemic stroke patients with atrial fibrillation.  Neurol Res. 2010;32(4):353-358PubMedArticle
12.
Maagh P, Butz T, Wickenbrock I,  et al.  New-onset versus chronic atrial fibrillation in acute myocardial infarction: differences in short- and long-term follow-up.  Clin Res Cardiol. 2011;100(2):167-175PubMedArticle
13.
Adams HP Jr, del Zoppo G, Alberts MJ,  et al; American Heart Association; American Stroke Association Stroke Council; Clinical Cardiology Council; Cardiovascular Radiology and Intervention Council; Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups.  Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.  Stroke. 2007;38(5):1655-1711PubMedArticle
14.
Madden KP, Karanjia PN, Adams HP Jr, Clarke WR. Accuracy of initial stroke subtype diagnosis in the TOAST study. Trial of ORG 10172 in Acute Stroke Treatment.  Neurology. 1995;45(11):1975-1979PubMedArticle
15.
Hacke W, Kaste M, Fieschi C,  et al; The European Cooperative Acute Stroke Study (ECASS).  Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke.  JAMA. 1995;274(13):1017-1025PubMedArticle
16.
Bonita R, Beaglehole R. Recovery of motor function after stroke.  Stroke. 1988;19(12):1497-1500PubMedArticle
17.
Rathore SS, Berger AK, Weinfurt KP,  et al.  Acute myocardial infarction complicated by atrial fibrillation in the elderly: prevalence and outcomes.  Circulation. 2000;101(9):969-974PubMed
18.
Kinjo K, Sato H, Sato H,  et al; Osaka Acute Coronary Insufficiency Study (OACIS) Group.  Prognostic significance of atrial fibrillation/atrial flutter in patients with acute myocardial infarction treated with percutaneous coronary intervention.  Am J Cardiol. 2003;92(10):1150-1154PubMedArticle
19.
Shi ZS, Loh Y, Walker G, Duckwiler GR.MERCI and Multi MERCI Investigators.  Endovascular thrombectomy for acute ischemic stroke in failed intravenous tissue plasminogen activator versus non-intravenous tissue plasminogen activator patients: revascularization and outcomes stratified by the site of arterial occlusions.  Stroke. 2010;41(6):1185-1192PubMedArticle
20.
Kimura K, Iguchi Y, Yamashita S, Shibazaki K, Kobayashi K, Inoue T. Atrial fibrillation as an independent predictor for no early recanalization after IV-t-PA in acute ischemic stroke.  J Neurol Sci. 2008;267(1-2):57-61PubMedArticle
21.
Ogata J, Yutani C, Otsubo R,  et al.  Heart and vessel pathology underlying brain infarction in 142 stroke patients.  Ann Neurol. 2008;63(6):770-781PubMedArticle
22.
Marder VJ, Chute DJ, Starkman S,  et al.  Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke.  Stroke. 2006;37(8):2086-2093PubMedArticle
23.
Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation.  Eur Heart J. 2010;31(8):967-975PubMedArticle
24.
Seet RC, Friedman PA, Rabinstein AA. Prolonged rhythm monitoring for the detection of occult paroxysmal atrial fibrillation in ischemic stroke of unknown cause.  Circulation. 2011;124(4):477-486PubMedArticle
25.
Elijovich L, Josephson SA, Fung GL, Smith WS. Intermittent atrial fibrillation may account for a large proportion of otherwise cryptogenic stroke: a study of 30-day cardiac event monitors.  J Stroke Cerebrovasc Dis. 2009;18(3):185-189PubMedArticle
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