Effect of Intravenous Thrombolysis on Stroke Associated with Atrial Fibrillation Visnja Padjen, MD,* Dejana Jovanovic, MD, PhD,*† Ivana Berisavac, MD,† Marko Ercegovac, MD, PhD,*† Maja Stefanovic Budimkic, MD,* Predrag Stanarcevic, MD,* and Ljiljana Beslac Bumbasirevic, MD, PhD*†
Background: Data based on randomized clinical trials regarding the efficacy and safety of intravenous thrombolysis (IVT) versus placebo or any other antithrombotic agent in the treatment of stroke associated with atrial fibrillation (AF) are unavailable. Methods: Prospectively collected data on AF-associated stroke patients treated in a 3-year period were analyzed to assess the effect of IVT treatment. Outcome measures were modified Rankin Scale (mRS) score for functional outcome, death, and symptomatic intracerebral hemorrhage (sICH). Results: Of 787 patients diagnosed with an acute ischemic stroke in the observed period, 131 (16.6%) had AF. Multivariate logistic regression analysis after adjustment for confounders demonstrated that independent predictors of excellent outcome (mRS 0-1) in patients with AF-associated stroke were lower baseline National Institutes of Health Stroke Scale [NIHSS] score (adjusted odds ratio [adjOR], .87; 95% confidence interval [CI], 0.81-.94; P 5 .000) and the use of IVT (adjOR, 5.31; 95% CI, 1.90-14.82; P 5 .001), whereas independent predictors of death were higher baseline NIHSS score (adjOR, 1.07; 95% CI, 1.02-1.12; P 5 .003), previous stroke (adjOR, 4.11; 95% CI, 1.49-11.35; P 5 .006), absence of IVT use (adjOR, .19; 95% CI, .05-.77; P 5 .021), sICH (adjOR, 18.52; 95% CI, 1.59-215.37; P 5 .020), and higher serum glucose levels (adjOR, 1.26; 95% CI, 1.06-1.50; P 5.008). Thrombolyzed patients with AF were less severe at baseline and were less likely to have NIHSS .18. They were more likely to have excellent and good functional outcome (mRS 0-2) whereas less likely to have death as outcome at 3 months. Thrombolyzed AF patients had constantly lower probability of death regardless of the baseline NIHSS score values. Conclusions: These results should encourage the use of IVT in AF-associated strokes. Key Words: Stroke—atrial fibrillation—intravenous thrombolysis—outcome. Ó 2014 by National Stroke Association
From the *Neurology Clinic, Clinical Centre of Serbia, Belgrade; and †Medical Faculty, University of Belgrade, Belgrade, Serbia. Received February 19, 2014; revision received March 31, 2014; accepted April 30, 2014. The study was performed in the Department for Emergency Neurology of the Neurology Clinic, Clinical Centre of Serbia. D.J. and L.B.B. have received funding for travel or speaker honoraria from Boehringer Ingelheim (100001003). L.B.B has also received funding for travel or speaker honoraria from Actavis, Bayer (100004326), Pfizer Inc, and Sanofi-aventis. Address correspondence to Visnja Padjen, MD, Neurology Clinic, Clinical Centre of Serbia, Dr Subotica 6, 11000 Belgrade, Serbia. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.04.035
Introduction Atrial fibrillation (AF) is the most prevalent sustained hearth rhythm disorder, which is associated with severe consequences that include heart failure, stroke, reduced quality of life, poor mental health, and death.1 Around 2% of world population has AF and the situation is predicted to worsen because it is expected that the number of people with AF will double by 2050.2,3 AF is an independent risk factor for stroke and thromboembolism, which increases the stroke risk by 5-fold and results in an independent increase in mortality per se.4 It is estimated that AF is responsible for approximately 15%-20% of all strokes.5 AF-associated strokes are more severe,6 more
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often fatal, and more likely to lead to disability. They are also more likely to increase costs9 and extended hospital care compared with non-AF strokes.6 Intravenous thrombolysis (IVT) is the only approved therapy in patients with acute ischemic stroke presenting within 4.5 hours after symptom onset.10 However, data about its efficacy in the treatment of AF-associated strokes is still scarce because there have no’t been many studies that were analyzing the issue whether stroke patients with AF are obtaining significant benefit from thrombolysis in comparison with non thrombolyzed stroke patients with AF. In randomized controlled trials of IVTuse in treatment of ischemic stroke, baseline characteristics and outcomes of AF patients who were thrombolyzed have been detailed in only few trials.11-13 However, their results are conflicting with a non-significant trend in favor of placebo in ‘‘Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III)’’ trial,12 in favor of IVT in ‘‘The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke [IST-3])’’ trial,11 and no effect of the treatment in ‘‘Tissue Plasminogen Activator for Acute Ischemic Stroke (NINDS)’’ trial.13 Some studies that were analyzing in more detail, the baseline characteristics and outcomes of AF-associated stroke patients (with thrombolyzed and non-thrombolyzed ones included), have also reported contradictory results.14-16 In Virtual International Stroke Trials Archive (VISTA) study, of 1631 AF patients with ischemic stroke, 639 received IVT. AF patients had more severe clinical deficits, were older than non-AF patients, and there was a benefit of IVT administration that was registered.14 In another retrospective study that compared 22 AF patients who received IVT with 44 AF patients who did not, there was an association with a favorable outcome in thrombolyzed patients.15 On the other hand, the study of Saposnik et al16 that included 2185 patients with AFassociated stroke, from which 316 were thrombolyzed, has found no benefit of IVT use in patients with AF. The aims of our study were the following: (1) to analyze baseline characteristics of AF patients with stroke and (2) to test the hypothesis that stroke patients with AF who receive IVT have better outcomes in comparison with non-thrombolyzed AF patients.
Materials and Methods We analyzed prospectively collected data of patients with AF-associated stroke who were treated in the Department for Emergency Neurology of Neurology Clinic, Clinical Centre of Serbia, from January 2009 to June 2012. For the study, a specially designed protocol was used.
Setting The general organization of this stroke center has already been described.17
Inclusion and Noninclusion Criteria Inclusion and exclusion criteria were those of the NINDS recombinant tissue plasminogen activator stroke protocol.18 To be indicated for IVT administration patients had to have the following: (1) an acute ischemic stroke with a clearly defined time of onset; (2) an acute neurologic deficit expected to result in significant long-term disability; and (3) a baseline computed tomographic scan of the brain showing no hemorrhage or wellestablished acute infarct.18 IVT was performed according to the current guideline up to a 4.5-hour time window for hemispheric stroke and up to 12 hours for posterior circulation stroke.19 Eligible patients received 0.9 mg of alteplase per kilogram of body weight (with a maximum dose 90 mg), administrated intravenously.19
Assessment of AF In all patients medical history was recorded, an electrocardiogram (ECG) at admission was performed as well as a 48-72 hours continuous ECG monitoring and, if necessary because of the clinical symptoms, additional ECG recordings. AF was classified as previously known or de novo AF. AF was considered as previously known in cases where previous ECG with AF or atrial flutter was seen by a stroke team’s physician or when there was a report of a cardiologist stating that AF had been previously detected on ECG or Holter ECG. AF was considered as de novo in cases when there was no medical history of previous AF or atrial flutter but this was found on either ECG recorded in the emergency department on admission or during hospitalization (on the 48-72 hours continuous ECG monitoring).
Clinical Assessment The pretreatment stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) score18 just before IVT administration and after 7 days. The outcomes at 3 months were assessed with the modified Rankin Scale (mRS) score.20 All assessments were made by a senior neurologist. In survivors, when the visit after 3 months was not possible it was replaced by a telephone interview with the patient, caregiver, local neurologist, or general practitioner. The analyses of computed tomographic scans were performed by a neuroradiologist.
End Points The primary end point was the proportion of patients who had an excellent outcome (defined as a mRS score of 0 or 1 at 3 months or similar to the pre-stroke mRS). Secondary end points were as follows: (1) after 7 days: symptomatic intracerebral hemorrhage (sICH, defined according to the ECASS III definition)10 and death and (2) after 3 months: good outcome (defined as a mRS 0-2) and death.
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Statistical Analysis
Results
All gathered data were analyzed by using the methods of descriptive and analytic statistics. Median values and interquartile ranges were used. The comparison of categorical variables between groups was performed with the chi square test with Yates’correction or Fisher exact test when appropriate, whereas continuous variables were compared with the Mann-Whitney U test. The odds ratio (OR) and 95% confidence interval (CI) were obtained. Three logistic regression analyses were performed21 to study the relationships between independent variables (eg, baseline NIHSS score, IVT) and outcome parameters: excellent outcome, good outcome, and death (as dependent variables), which were evaluated at 3 months. Adjusted odds ratio (adjOR) and 95% CI were calculated from the logistic regression analyses. The models were adjusted for all variables with P value ,.1 in the univariate analyses. The Statistical Package for the Social Sciences (SPSS) software for Windows (version 17.0) was used for statistical analysis.
General Features Of 787 patients with an acute stroke treated at the Department for Emergency neurology, in a 3-year period, 131 (16.6%) had AF and were included in the study. Of these, 34 patients (25.9%) received IVT and 97 (74.1%) were not thrombolyzed. Demographic and baseline characteristics of the study population are detailed in Table 1. Patients who received IVT were less likely to have NIHSS score . 18, to be on previous oral anticoagulant therapy (OAT), and to have previous stroke. On the other hand, they were more likely to be current smokers.
Comparison of Outcomes in Thrombolyzed and Nonthrombolyzed AF Patients with Stroke Comparison of outcomes between patients treated with IVT and those who were not thrombolyzed is presented in Table 2.
Table 1. Demographic and baseline characteristics of the study population of AF patients with stroke treated and not treated by IVT during the study period. Unless specified, values are number of patients Characteristics Demographic characteristics Male gender, n (%) Age, y* Age .75 y, n (%) Age ,45 y, n (%) Medical history, n (%) Cardiomyopathy Arterial hypertension Diabetes mellitus Previously known AF Hypercholesterolemia Currently smoking Previous stroke Other previous vascular illness (myocardial infarction, peripheral artery disease, and so forth) Oral anticoagulation before stroke in patients with previous AF Antiplatelet agents before stroke Clinical and biological characteristics Baseline NIHSS* NIHSS .18, n (%) SBP* DBP* MBP* Blood glucose (mmol/L)* Hemoglobin (g/L)* Number of platelets (1039/L)* D-dimer (mg/L FEU)* Fibrinogen (g/L)*
IVT, N 534
Non-IVT, N 597
P values
OR (95% CI)
20 (58.8) 68 (61-75) 7 (20.6) 1 (2.9)
50 (51.5) 72 (64-78) 35 (36.1) 5 (2.2)
.464 .065 .096 .595
.74 (.33-1.64)
12 (35.3) 32 (94.1) 7 (20.6) 19 (55.9) 10 (29.4) 13 (38.2) 4 (11.8) 14 (41.2)
29 (29.9) 85 (87.6) 24 (24.7) 61 (62.9) 37 (38.8) 20 (20.6) 33 (34.0) 38 (39.2)
.559 .293 .624 .293 .064 .042 .013 .837
1.27 (.56-2.92) 2.26 (.48-10.66) .79 (.30-2.04) .65 (.29-1.44)
2 (5.9)
33 (34.0)
.001
.12 (.03-.54)
15 (44.1)
35 (36.1)
.407
1.39 (.63-3.09)
14 (5-23) 36 (37.1) 150 (135-170) 90 (80-100) 106.67 (100-124) 6.8 (5.9-8.4) 140 (127-149) 219 (174-271) 2.5 (.90-15.29) 4.8 (3.7-7.42)
.616 .006 .240 .350 .214 .985 .581 .073 .781 .267
11 (8-16) 4 (11.8) 155 (140-164) 90 (80-100) 110 (105-120) 6.65 (5.87-8.6) 138 (128-147) 194 (160-241) 2.98 (.81-10.10) 4.0 (3.4-5.4)
.46 (.18-1.16) .56 (.06-4.95)
2.38 (1.02-5.57) .26 (.08-.79) 1.09 (.49-2.41)
.22 (.07-.69)
Abbreviations: AF, atrial fibrillation; CI, confidence interval; DBP, diastolic blood pressure; IVT, intravenous thrombolysis; MBP, median blood pressure; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; SBP, systolic blood pressure; FEU, fibrinogen-equivalent units. *Values are median (interquartile range).
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Table 2. Comparison of outcomes between AF patients treated with IVT and not treated with IVT Outcomes
IVT, N 5 34
Non-IVT, N 5 97
OR (95% CI)
Asymptomatic haemorrhagic transformation Symptomatic hemorrhagic transformation, n (%) Death at 7 days, n (%) Excellent outcome (mRS 0-1) at 3 months, n (%) Good outcome (mRS 0-2) at 3 months, n (%) Death at 3 months, n (%)
4 (11.8) 2 (5.9) 1 (2.9) 20 (58.8) 22 (64.7) 5 (14.7)
13 (13.4) 4 (4.1) 17 (17.5) 23 (23.8) 27 (27.8) 44 (45.4)
.86 (.26-2.84) 1.45 (.25-8.31) .143 (.18-1.12) 4.59 (2.00-10.52) 4.75 (2.07-10.92) .21 (.07-.58)
Abbreviations: CI, confidence interval; IVT, intravenous thrombolysis; mRS, modified Rankin scale score; OR, odds ratio.
Outcomes after 7 days were similar in both groups. At 3 months, patients who received IVT were more likely to have excellent outcome and good outcome compared with nonthrombolyzed patients. Also, they were less likely to have death as outcome after 3 months in comparison with non-thrombolyzed patients. mRS values at 3 months in patients treated with IVT and those who were not treated with IVT are presented in Figure 1.
The statistical analysis has shown that the predicted probability of excellent functional outcome at 3 months is higher in the group of IVT-treated patients in comparison with nonthrombolyzed ones when the NIHSS score is ,18, whereas in cases of NIHSS .18 this probability is similar for both groups and it is low (NIHSS score: P 5 .000, IVT: P 5 .030; Fig 2, A.). On the other hand, the probability of death as outcome at 3 months in both cases NIHSS ,18 and NIHSS .18 is lower in thrombolyzed group of patients (NIHSS score: P 5 .002, IVT: P 5 .029; Fig 2, B).
Predictors of Outcome for Patients with AF-associated Stroke Independent variables associated with excellent outcome at 3 months were lower baseline NIHSS score (adjOR, .87; 95% CI, .81-.94; P 5 .000) and the use of IVT (adjOR, 5.31; 95% CI, 1.90-14.82; P 5 .001; Table 3). Independent variables associated with good outcome at 3 months were lower baseline NIHSS score (adjOR, .90; 95% CI, .84-.95; P 5 .000) and the use of IVT (adjOR, 4.82; 95% CI, 1.73-13.40; P 5 .003; Table 3). Independent variables associated with death at 3 months were higher baseline NIHSS score (adjOR, 1.07; 95% CI, 1.02-1.12; P 5 .003), previous stroke (adjOR, 4.11; 95% CI, 1.49-11.35; P 5 .006), absence of IVT use (adjOR, .19; 95% CI, .05-.77; P 5 .021), sICH (adjOR, 18.52; 95% CI, 1.59-215.37; P 5 .020), and higher serum glucose levels (adjOR, 1.26; 95% CI, 1.06-1.50; P 5 .008; Table 3).
Discussion Intravenous administration of recombinant tissue plasminogen activator or IVT is the only approved treatment for acute ischemic stroke. However, data about its efficacy in the treatment of AF-associated strokes is still scarce. The main explanation for low proportion of thrombolyzed AF patients in our study can be found in the fact that many of AF patients with stroke could not have been treated with IVT because of the late arrival at the emergency department or, in smaller number of cases, because of their ongoing OAT, which resulted with baseline International Normalized Ratio (INR) $1.7. Our study has shown that, in comparison with nonthrombolyzed AF patients, those AF patients who received IVT were less severe at baseline, were more likely to have
Figure 1. Functional outcome of patients with AF-associated stroke assessed by using modified Rankin Scale score values at 3 months. Abbreviations: AF, atrial fibrillation; IVT, intravenous thrombolysis.
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Table 3. Multivariate analysis of outcomes in patients with AF-associated stroke (odds adjusted for all variables with P , .1 in the univariate analysis) Predictors for
Excellent outcome (mRS 0-1)
Good outcome (mRS 0-2)
Death (mRS 6)
Age NIHSS score Serum glucose (mmol/L) Diabetes mellitus Hypercholesterolemia Current smoking Previous stroke Previous vascular illness IVT aICH sICH
1.02 (.97-1.06), .512 .87 (.81-.94), .000 .94 (.79-1.13), .525 .52 (.14-2.01), .345 2.26 (.97-5.24), .058 NQ .84 (.26-2.76), .777 NQ 5.31 (1.90-14.82), .001 NQ NQ
.99 (.95-1.03), .472 .90 (.84-.95), .000 .91 (.77-1.08), .267 1.03 (.29-3.69), .970 2.01 (.88-4.61), .098 1.78 (.62-5.09), .287 1.14 (.38-3.41), .815 .59 (.23-1.54), .282 4.82 (1.73-13.40), .003 NQ NQ
.97 (.93-1.02), .283 1.07 (1.02-1.12), .003 1.26 (1.06-1.50), .008 .90 (.20-4.07), .892 .40 (.15-1.11), .081 .50 (.11-2.24), .361 4.11 (1.49-11.35), .006 NQ .19 (.05-.77), .021 .38 (.07-2.10), .268 18.52 (1.59-215.37), .020
Abbreviations: aICH, asymptomatic intracerebral hemorrhage; IVT, intravenous thrombolysis; mRS, modified Rankin scale score; NIHSS, National Institutes of Health Stroke Scale; NQ, not qualified in the univariate analysis; sICH, symptomatic intracerebral haemorrhage. Data are odds ratio (95% confidence interval), P value.
excellent functional outcome (58.8% vs. 23.8%) and good functional outcome (64.7% vs. 27.8%) at 3 months, and were less likely to have death as functional outcome at 3 months (14.7% vs. 45.4%). Our study has also reported that among all stroke patients with AF: (1) those having lower baseline NIHSS score and the use of IVT were independent predictors of excellent as well as good functional outcome at 3 months; (2) higher baseline NIHSS score, previous stroke, higher serum glucose levels, absence of IVT use, and presence of sICH were independent predictors of death at 3 months; and (3) the probability of death as outcome remains constantly lower in case of thrombolyzed AF patients compared with non-thrombolyzed ones, regardless of the value of baseline NIHSS score. Our study population has similar baseline characteristics as those of patients reported in VISTA trial and the study of Zhang et al.14,15 Furthermore, regarding the outcomes, similar results have been registered. In the
Figure 2. Predicted probability of stroke outcome at 3 months in thrombolyzed and nonthrombolyzed patients with AFassociated stroke regarding their baseline National Institutes of Health Stroke Scale score. (A) Excellent functional outcome (modified Rankin Scale score 0-1); (B) death. Abbreviations: AF, atrial fibrillation; IVT, intravenous thrombolysis; NIHSS, National Institutes of Health Stroke Scale.
VISTA trial, the proportion for excellent outcome in IVT versus non-IVT group was 24.4% versus 23.6% (OR [95% CI], 1.42 [1.08-1.85]),14 whereas in our group, it was 58.8% versus 23.8% (OR [95% CI], 4.59 [2.00-10.52]). Regarding the good outcome in the VISTA trial it was 33.0% versus 32.1% (OR [95% CI], 1.43 [1.11-1.83]),14 whereas in our group, it was 64.7% versus 27.8% (OR [95% CI], 4.75 [2.07-10.92]). The study of Zhang et al15 has also found the statistical significance between 2 groups regarding good outcome (36% vs. 14%, P 5 .033). These results demonstrate that in quoted studies, there were significantly higher probabilities for better outcome (excellent and/or good) in the groups of thrombolyzed patients. However, the results of our study have shown that two thirds of thrombolyzed patients have good outcome in the case that they receive IVT, which is higher than in other 2 studies. Regarding death as outcome at 3 months, in the study of Zhang et al,15 death occurred in 18% of thrombolyzed stroke patients with AF, whereas
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in the VISTA trial, it occurred in 21.8%. In our study, the proportion of death at 3 months in the group of IVTtreated patients was 14.7%, which is slightly lower than in the 2 previously mentioned studies. Despite the fact that direct comparison between these 3 studies cannot be made, mainly because of the different settings, all these studies are in accordance that there is a benefit of the use of IVT in AF-associated strokes. The reason for this greater efficacy of IVT in our group in comparison with 2 other studies is not easy to find. On one hand, our patients were younger compared with those from VISTA trial (68 vs. 74.2 years of age)14 and had lower baseline NIHSS score (11 vs. 15)14, which could be an explanation regarding this trial. Furthermore, they were of similar age in comparison with the study of Zhang et al15 (68 vs. 68.3 years of age) and also with the similar baseline NIHSS score (11 vs. 12). On the other hand, Saposnik et al16 reported that the proportion for excellent outcome in IVTversus non-IVT–treated AF patients was 9.8% versus 19.8%, for good outcome 16.1% versus 32.9%, whereas for death it was 26.3% versus 18.1%. Patients with AFassociated stroke in this study were older from those in our group (79 vs. 68 years of age). The objective of previously mentioned study was to evaluate clinical outcomes in stroke patients with and without AF, while regarding the analysis of IVT- versus non-IVT–treated AF patients, only data about the outcome has been reported. Therefore, direct and more detailed comparison between our 2 studies cannot be made. The main predictors for excellent and good outcomes were having lower baseline NIHSS score and the use of IVT, whereas having higher baseline NIHSS score, nonuse of IVT as well as the presence of additional risk factors (previous stroke and high serum glucose levels), and sICH were main predictors of death. These findings are in accordance with reports of the studies that were analyzing predictors of stroke outcomes.22 It is important to stress out that our study has shown that the probability of death as outcome remains constantly lower in cases of thrombolyzed AF patients compared with nonthrombolyzed ones, regardless of the value of baseline NIHSS score. An important issue that can influence the administration of IVT in stroke patients with AF is the previous use of OAT. Two large studies were examining the issue of the evaluation of risks of intracranial hemorrhage among stroke patients who were on previous OAT and were treated with IVT. One study has reported that in these patients (who had PT INR# 1.7) the use of thrombolysis was not found to be associated with increased sICH risk,23 whereas another study found a statistically significant increase of sICH among these patients,24 in comparison with nonwarfarin-treated patients. Unfortunately, our study could not lead to a certain conclusion regarding this controversy because there were only 2 patients who were on previous OAT and thrombolyzed afterward.
Conclusion Despite the fact that only 131 consecutive patients were analyzed and that there is a clear target for the future to reproduce this survey with a larger sample size, the results of our study suggest that stroke patients with AF do obtain benefit from thrombolysis. Therefore, the authors hope that this would be an extra tray on the scale in favor of the use of IVT in these patients.
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management of ischemic stroke and transient ischemic attack 2008. Cerebrovasc Dis 2008;25:457-507. van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604-607. Bendel R, Afifi A. Comparison of stopping rules in forward regression. J Am Stat Ass 1977;72:46-53. Henon H, Godefroy O, Leys D, et al. Early predictors of death and disability after acute cerebral ischemic event. Stroke 1995;26:392-398. Xian Y, Liang L, Smith E, et al. Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. JAMA 2012;307:2600-2608. Ruecker M, Matosevic B, Willeit P, et al. Subtherapeutic warfarin therapy entails an increased bleeding risk after stroke thrombolysis. Neurology 2012;79:31-38.
Background: Data based on randomized clinical trials regarding the efficacy and safety of intravenous thrombolysis (IVT) versus placebo or any other antithrombotic agent in the treatment of stroke associated with atrial fibrillation (AF) are unavailable. Methods: Prospectively collected data on AF-associated stroke patients treated in a 3-year period were analyzed to assess the effect of IVT treatment. Outcome measures were modified Rankin Scale (mRS) score for functional outcome, death, and symptomatic intracerebral hemorrhage (sICH). Results: Of 787 patients diagnosed with an acute ischemic stroke in the observed period, 131 (16.6%) had AF. Multivariate logistic regression analysis after adjustment for confounders demonstrated that independent predictors of excellent outcome (mRS 0-1) in patients with AF-associated stroke were lower baseline National Institutes of Health Stroke Scale [NIHSS] score (adjusted odds ratio [adjOR], .87; 95% confidence interval [CI], 0.81-.94; P 5 .000) and the use of IVT (adjOR, 5.31; 95% CI, 1.90-14.82; P 5 .001), whereas independent predictors of death were higher baseline NIHSS score (adjOR, 1.07; 95% CI, 1.02-1.12; P 5 .003), previous stroke (adjOR, 4.11; 95% CI, 1.49-11.35; P 5 .006), absence of IVT use (adjOR, .19; 95% CI, .05-.77; P 5 .021), sICH (adjOR, 18.52; 95% CI, 1.59-215.37; P 5 .020), and higher serum glucose levels (adjOR, 1.26; 95% CI, 1.06-1.50; P 5.008). Thrombolyzed patients with AF were less severe at baseline and were less likely to have NIHSS .18. They were more likely to have excellent and good functional outcome (mRS 0-2) whereas less likely to have death as outcome at 3 months. Thrombolyzed AF patients had constantly lower probability of death regardless of the baseline NIHSS score values. Conclusions: These results should encourage the use of IVT in AF-associated strokes. Key Words: Stroke—atrial fibrillation—intravenous thrombolysis—outcome. Ó 2014 by National Stroke Association
From the *Neurology Clinic, Clinical Centre of Serbia, Belgrade; and †Medical Faculty, University of Belgrade, Belgrade, Serbia. Received February 19, 2014; revision received March 31, 2014; accepted April 30, 2014. The study was performed in the Department for Emergency Neurology of the Neurology Clinic, Clinical Centre of Serbia. D.J. and L.B.B. have received funding for travel or speaker honoraria from Boehringer Ingelheim (100001003). L.B.B has also received funding for travel or speaker honoraria from Actavis, Bayer (100004326), Pfizer Inc, and Sanofi-aventis. Address correspondence to Visnja Padjen, MD, Neurology Clinic, Clinical Centre of Serbia, Dr Subotica 6, 11000 Belgrade, Serbia. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.04.035
Introduction Atrial fibrillation (AF) is the most prevalent sustained hearth rhythm disorder, which is associated with severe consequences that include heart failure, stroke, reduced quality of life, poor mental health, and death.1 Around 2% of world population has AF and the situation is predicted to worsen because it is expected that the number of people with AF will double by 2050.2,3 AF is an independent risk factor for stroke and thromboembolism, which increases the stroke risk by 5-fold and results in an independent increase in mortality per se.4 It is estimated that AF is responsible for approximately 15%-20% of all strokes.5 AF-associated strokes are more severe,6 more
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often fatal, and more likely to lead to disability. They are also more likely to increase costs9 and extended hospital care compared with non-AF strokes.6 Intravenous thrombolysis (IVT) is the only approved therapy in patients with acute ischemic stroke presenting within 4.5 hours after symptom onset.10 However, data about its efficacy in the treatment of AF-associated strokes is still scarce because there have no’t been many studies that were analyzing the issue whether stroke patients with AF are obtaining significant benefit from thrombolysis in comparison with non thrombolyzed stroke patients with AF. In randomized controlled trials of IVTuse in treatment of ischemic stroke, baseline characteristics and outcomes of AF patients who were thrombolyzed have been detailed in only few trials.11-13 However, their results are conflicting with a non-significant trend in favor of placebo in ‘‘Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III)’’ trial,12 in favor of IVT in ‘‘The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke [IST-3])’’ trial,11 and no effect of the treatment in ‘‘Tissue Plasminogen Activator for Acute Ischemic Stroke (NINDS)’’ trial.13 Some studies that were analyzing in more detail, the baseline characteristics and outcomes of AF-associated stroke patients (with thrombolyzed and non-thrombolyzed ones included), have also reported contradictory results.14-16 In Virtual International Stroke Trials Archive (VISTA) study, of 1631 AF patients with ischemic stroke, 639 received IVT. AF patients had more severe clinical deficits, were older than non-AF patients, and there was a benefit of IVT administration that was registered.14 In another retrospective study that compared 22 AF patients who received IVT with 44 AF patients who did not, there was an association with a favorable outcome in thrombolyzed patients.15 On the other hand, the study of Saposnik et al16 that included 2185 patients with AFassociated stroke, from which 316 were thrombolyzed, has found no benefit of IVT use in patients with AF. The aims of our study were the following: (1) to analyze baseline characteristics of AF patients with stroke and (2) to test the hypothesis that stroke patients with AF who receive IVT have better outcomes in comparison with non-thrombolyzed AF patients.
Materials and Methods We analyzed prospectively collected data of patients with AF-associated stroke who were treated in the Department for Emergency Neurology of Neurology Clinic, Clinical Centre of Serbia, from January 2009 to June 2012. For the study, a specially designed protocol was used.
Setting The general organization of this stroke center has already been described.17
Inclusion and Noninclusion Criteria Inclusion and exclusion criteria were those of the NINDS recombinant tissue plasminogen activator stroke protocol.18 To be indicated for IVT administration patients had to have the following: (1) an acute ischemic stroke with a clearly defined time of onset; (2) an acute neurologic deficit expected to result in significant long-term disability; and (3) a baseline computed tomographic scan of the brain showing no hemorrhage or wellestablished acute infarct.18 IVT was performed according to the current guideline up to a 4.5-hour time window for hemispheric stroke and up to 12 hours for posterior circulation stroke.19 Eligible patients received 0.9 mg of alteplase per kilogram of body weight (with a maximum dose 90 mg), administrated intravenously.19
Assessment of AF In all patients medical history was recorded, an electrocardiogram (ECG) at admission was performed as well as a 48-72 hours continuous ECG monitoring and, if necessary because of the clinical symptoms, additional ECG recordings. AF was classified as previously known or de novo AF. AF was considered as previously known in cases where previous ECG with AF or atrial flutter was seen by a stroke team’s physician or when there was a report of a cardiologist stating that AF had been previously detected on ECG or Holter ECG. AF was considered as de novo in cases when there was no medical history of previous AF or atrial flutter but this was found on either ECG recorded in the emergency department on admission or during hospitalization (on the 48-72 hours continuous ECG monitoring).
Clinical Assessment The pretreatment stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) score18 just before IVT administration and after 7 days. The outcomes at 3 months were assessed with the modified Rankin Scale (mRS) score.20 All assessments were made by a senior neurologist. In survivors, when the visit after 3 months was not possible it was replaced by a telephone interview with the patient, caregiver, local neurologist, or general practitioner. The analyses of computed tomographic scans were performed by a neuroradiologist.
End Points The primary end point was the proportion of patients who had an excellent outcome (defined as a mRS score of 0 or 1 at 3 months or similar to the pre-stroke mRS). Secondary end points were as follows: (1) after 7 days: symptomatic intracerebral hemorrhage (sICH, defined according to the ECASS III definition)10 and death and (2) after 3 months: good outcome (defined as a mRS 0-2) and death.
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Statistical Analysis
Results
All gathered data were analyzed by using the methods of descriptive and analytic statistics. Median values and interquartile ranges were used. The comparison of categorical variables between groups was performed with the chi square test with Yates’correction or Fisher exact test when appropriate, whereas continuous variables were compared with the Mann-Whitney U test. The odds ratio (OR) and 95% confidence interval (CI) were obtained. Three logistic regression analyses were performed21 to study the relationships between independent variables (eg, baseline NIHSS score, IVT) and outcome parameters: excellent outcome, good outcome, and death (as dependent variables), which were evaluated at 3 months. Adjusted odds ratio (adjOR) and 95% CI were calculated from the logistic regression analyses. The models were adjusted for all variables with P value ,.1 in the univariate analyses. The Statistical Package for the Social Sciences (SPSS) software for Windows (version 17.0) was used for statistical analysis.
General Features Of 787 patients with an acute stroke treated at the Department for Emergency neurology, in a 3-year period, 131 (16.6%) had AF and were included in the study. Of these, 34 patients (25.9%) received IVT and 97 (74.1%) were not thrombolyzed. Demographic and baseline characteristics of the study population are detailed in Table 1. Patients who received IVT were less likely to have NIHSS score . 18, to be on previous oral anticoagulant therapy (OAT), and to have previous stroke. On the other hand, they were more likely to be current smokers.
Comparison of Outcomes in Thrombolyzed and Nonthrombolyzed AF Patients with Stroke Comparison of outcomes between patients treated with IVT and those who were not thrombolyzed is presented in Table 2.
Table 1. Demographic and baseline characteristics of the study population of AF patients with stroke treated and not treated by IVT during the study period. Unless specified, values are number of patients Characteristics Demographic characteristics Male gender, n (%) Age, y* Age .75 y, n (%) Age ,45 y, n (%) Medical history, n (%) Cardiomyopathy Arterial hypertension Diabetes mellitus Previously known AF Hypercholesterolemia Currently smoking Previous stroke Other previous vascular illness (myocardial infarction, peripheral artery disease, and so forth) Oral anticoagulation before stroke in patients with previous AF Antiplatelet agents before stroke Clinical and biological characteristics Baseline NIHSS* NIHSS .18, n (%) SBP* DBP* MBP* Blood glucose (mmol/L)* Hemoglobin (g/L)* Number of platelets (1039/L)* D-dimer (mg/L FEU)* Fibrinogen (g/L)*
IVT, N 534
Non-IVT, N 597
P values
OR (95% CI)
20 (58.8) 68 (61-75) 7 (20.6) 1 (2.9)
50 (51.5) 72 (64-78) 35 (36.1) 5 (2.2)
.464 .065 .096 .595
.74 (.33-1.64)
12 (35.3) 32 (94.1) 7 (20.6) 19 (55.9) 10 (29.4) 13 (38.2) 4 (11.8) 14 (41.2)
29 (29.9) 85 (87.6) 24 (24.7) 61 (62.9) 37 (38.8) 20 (20.6) 33 (34.0) 38 (39.2)
.559 .293 .624 .293 .064 .042 .013 .837
1.27 (.56-2.92) 2.26 (.48-10.66) .79 (.30-2.04) .65 (.29-1.44)
2 (5.9)
33 (34.0)
.001
.12 (.03-.54)
15 (44.1)
35 (36.1)
.407
1.39 (.63-3.09)
14 (5-23) 36 (37.1) 150 (135-170) 90 (80-100) 106.67 (100-124) 6.8 (5.9-8.4) 140 (127-149) 219 (174-271) 2.5 (.90-15.29) 4.8 (3.7-7.42)
.616 .006 .240 .350 .214 .985 .581 .073 .781 .267
11 (8-16) 4 (11.8) 155 (140-164) 90 (80-100) 110 (105-120) 6.65 (5.87-8.6) 138 (128-147) 194 (160-241) 2.98 (.81-10.10) 4.0 (3.4-5.4)
.46 (.18-1.16) .56 (.06-4.95)
2.38 (1.02-5.57) .26 (.08-.79) 1.09 (.49-2.41)
.22 (.07-.69)
Abbreviations: AF, atrial fibrillation; CI, confidence interval; DBP, diastolic blood pressure; IVT, intravenous thrombolysis; MBP, median blood pressure; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; SBP, systolic blood pressure; FEU, fibrinogen-equivalent units. *Values are median (interquartile range).
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Table 2. Comparison of outcomes between AF patients treated with IVT and not treated with IVT Outcomes
IVT, N 5 34
Non-IVT, N 5 97
OR (95% CI)
Asymptomatic haemorrhagic transformation Symptomatic hemorrhagic transformation, n (%) Death at 7 days, n (%) Excellent outcome (mRS 0-1) at 3 months, n (%) Good outcome (mRS 0-2) at 3 months, n (%) Death at 3 months, n (%)
4 (11.8) 2 (5.9) 1 (2.9) 20 (58.8) 22 (64.7) 5 (14.7)
13 (13.4) 4 (4.1) 17 (17.5) 23 (23.8) 27 (27.8) 44 (45.4)
.86 (.26-2.84) 1.45 (.25-8.31) .143 (.18-1.12) 4.59 (2.00-10.52) 4.75 (2.07-10.92) .21 (.07-.58)
Abbreviations: CI, confidence interval; IVT, intravenous thrombolysis; mRS, modified Rankin scale score; OR, odds ratio.
Outcomes after 7 days were similar in both groups. At 3 months, patients who received IVT were more likely to have excellent outcome and good outcome compared with nonthrombolyzed patients. Also, they were less likely to have death as outcome after 3 months in comparison with non-thrombolyzed patients. mRS values at 3 months in patients treated with IVT and those who were not treated with IVT are presented in Figure 1.
The statistical analysis has shown that the predicted probability of excellent functional outcome at 3 months is higher in the group of IVT-treated patients in comparison with nonthrombolyzed ones when the NIHSS score is ,18, whereas in cases of NIHSS .18 this probability is similar for both groups and it is low (NIHSS score: P 5 .000, IVT: P 5 .030; Fig 2, A.). On the other hand, the probability of death as outcome at 3 months in both cases NIHSS ,18 and NIHSS .18 is lower in thrombolyzed group of patients (NIHSS score: P 5 .002, IVT: P 5 .029; Fig 2, B).
Predictors of Outcome for Patients with AF-associated Stroke Independent variables associated with excellent outcome at 3 months were lower baseline NIHSS score (adjOR, .87; 95% CI, .81-.94; P 5 .000) and the use of IVT (adjOR, 5.31; 95% CI, 1.90-14.82; P 5 .001; Table 3). Independent variables associated with good outcome at 3 months were lower baseline NIHSS score (adjOR, .90; 95% CI, .84-.95; P 5 .000) and the use of IVT (adjOR, 4.82; 95% CI, 1.73-13.40; P 5 .003; Table 3). Independent variables associated with death at 3 months were higher baseline NIHSS score (adjOR, 1.07; 95% CI, 1.02-1.12; P 5 .003), previous stroke (adjOR, 4.11; 95% CI, 1.49-11.35; P 5 .006), absence of IVT use (adjOR, .19; 95% CI, .05-.77; P 5 .021), sICH (adjOR, 18.52; 95% CI, 1.59-215.37; P 5 .020), and higher serum glucose levels (adjOR, 1.26; 95% CI, 1.06-1.50; P 5 .008; Table 3).
Discussion Intravenous administration of recombinant tissue plasminogen activator or IVT is the only approved treatment for acute ischemic stroke. However, data about its efficacy in the treatment of AF-associated strokes is still scarce. The main explanation for low proportion of thrombolyzed AF patients in our study can be found in the fact that many of AF patients with stroke could not have been treated with IVT because of the late arrival at the emergency department or, in smaller number of cases, because of their ongoing OAT, which resulted with baseline International Normalized Ratio (INR) $1.7. Our study has shown that, in comparison with nonthrombolyzed AF patients, those AF patients who received IVT were less severe at baseline, were more likely to have
Figure 1. Functional outcome of patients with AF-associated stroke assessed by using modified Rankin Scale score values at 3 months. Abbreviations: AF, atrial fibrillation; IVT, intravenous thrombolysis.
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Table 3. Multivariate analysis of outcomes in patients with AF-associated stroke (odds adjusted for all variables with P , .1 in the univariate analysis) Predictors for
Excellent outcome (mRS 0-1)
Good outcome (mRS 0-2)
Death (mRS 6)
Age NIHSS score Serum glucose (mmol/L) Diabetes mellitus Hypercholesterolemia Current smoking Previous stroke Previous vascular illness IVT aICH sICH
1.02 (.97-1.06), .512 .87 (.81-.94), .000 .94 (.79-1.13), .525 .52 (.14-2.01), .345 2.26 (.97-5.24), .058 NQ .84 (.26-2.76), .777 NQ 5.31 (1.90-14.82), .001 NQ NQ
.99 (.95-1.03), .472 .90 (.84-.95), .000 .91 (.77-1.08), .267 1.03 (.29-3.69), .970 2.01 (.88-4.61), .098 1.78 (.62-5.09), .287 1.14 (.38-3.41), .815 .59 (.23-1.54), .282 4.82 (1.73-13.40), .003 NQ NQ
.97 (.93-1.02), .283 1.07 (1.02-1.12), .003 1.26 (1.06-1.50), .008 .90 (.20-4.07), .892 .40 (.15-1.11), .081 .50 (.11-2.24), .361 4.11 (1.49-11.35), .006 NQ .19 (.05-.77), .021 .38 (.07-2.10), .268 18.52 (1.59-215.37), .020
Abbreviations: aICH, asymptomatic intracerebral hemorrhage; IVT, intravenous thrombolysis; mRS, modified Rankin scale score; NIHSS, National Institutes of Health Stroke Scale; NQ, not qualified in the univariate analysis; sICH, symptomatic intracerebral haemorrhage. Data are odds ratio (95% confidence interval), P value.
excellent functional outcome (58.8% vs. 23.8%) and good functional outcome (64.7% vs. 27.8%) at 3 months, and were less likely to have death as functional outcome at 3 months (14.7% vs. 45.4%). Our study has also reported that among all stroke patients with AF: (1) those having lower baseline NIHSS score and the use of IVT were independent predictors of excellent as well as good functional outcome at 3 months; (2) higher baseline NIHSS score, previous stroke, higher serum glucose levels, absence of IVT use, and presence of sICH were independent predictors of death at 3 months; and (3) the probability of death as outcome remains constantly lower in case of thrombolyzed AF patients compared with non-thrombolyzed ones, regardless of the value of baseline NIHSS score. Our study population has similar baseline characteristics as those of patients reported in VISTA trial and the study of Zhang et al.14,15 Furthermore, regarding the outcomes, similar results have been registered. In the
Figure 2. Predicted probability of stroke outcome at 3 months in thrombolyzed and nonthrombolyzed patients with AFassociated stroke regarding their baseline National Institutes of Health Stroke Scale score. (A) Excellent functional outcome (modified Rankin Scale score 0-1); (B) death. Abbreviations: AF, atrial fibrillation; IVT, intravenous thrombolysis; NIHSS, National Institutes of Health Stroke Scale.
VISTA trial, the proportion for excellent outcome in IVT versus non-IVT group was 24.4% versus 23.6% (OR [95% CI], 1.42 [1.08-1.85]),14 whereas in our group, it was 58.8% versus 23.8% (OR [95% CI], 4.59 [2.00-10.52]). Regarding the good outcome in the VISTA trial it was 33.0% versus 32.1% (OR [95% CI], 1.43 [1.11-1.83]),14 whereas in our group, it was 64.7% versus 27.8% (OR [95% CI], 4.75 [2.07-10.92]). The study of Zhang et al15 has also found the statistical significance between 2 groups regarding good outcome (36% vs. 14%, P 5 .033). These results demonstrate that in quoted studies, there were significantly higher probabilities for better outcome (excellent and/or good) in the groups of thrombolyzed patients. However, the results of our study have shown that two thirds of thrombolyzed patients have good outcome in the case that they receive IVT, which is higher than in other 2 studies. Regarding death as outcome at 3 months, in the study of Zhang et al,15 death occurred in 18% of thrombolyzed stroke patients with AF, whereas
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in the VISTA trial, it occurred in 21.8%. In our study, the proportion of death at 3 months in the group of IVTtreated patients was 14.7%, which is slightly lower than in the 2 previously mentioned studies. Despite the fact that direct comparison between these 3 studies cannot be made, mainly because of the different settings, all these studies are in accordance that there is a benefit of the use of IVT in AF-associated strokes. The reason for this greater efficacy of IVT in our group in comparison with 2 other studies is not easy to find. On one hand, our patients were younger compared with those from VISTA trial (68 vs. 74.2 years of age)14 and had lower baseline NIHSS score (11 vs. 15)14, which could be an explanation regarding this trial. Furthermore, they were of similar age in comparison with the study of Zhang et al15 (68 vs. 68.3 years of age) and also with the similar baseline NIHSS score (11 vs. 12). On the other hand, Saposnik et al16 reported that the proportion for excellent outcome in IVTversus non-IVT–treated AF patients was 9.8% versus 19.8%, for good outcome 16.1% versus 32.9%, whereas for death it was 26.3% versus 18.1%. Patients with AFassociated stroke in this study were older from those in our group (79 vs. 68 years of age). The objective of previously mentioned study was to evaluate clinical outcomes in stroke patients with and without AF, while regarding the analysis of IVT- versus non-IVT–treated AF patients, only data about the outcome has been reported. Therefore, direct and more detailed comparison between our 2 studies cannot be made. The main predictors for excellent and good outcomes were having lower baseline NIHSS score and the use of IVT, whereas having higher baseline NIHSS score, nonuse of IVT as well as the presence of additional risk factors (previous stroke and high serum glucose levels), and sICH were main predictors of death. These findings are in accordance with reports of the studies that were analyzing predictors of stroke outcomes.22 It is important to stress out that our study has shown that the probability of death as outcome remains constantly lower in cases of thrombolyzed AF patients compared with nonthrombolyzed ones, regardless of the value of baseline NIHSS score. An important issue that can influence the administration of IVT in stroke patients with AF is the previous use of OAT. Two large studies were examining the issue of the evaluation of risks of intracranial hemorrhage among stroke patients who were on previous OAT and were treated with IVT. One study has reported that in these patients (who had PT INR# 1.7) the use of thrombolysis was not found to be associated with increased sICH risk,23 whereas another study found a statistically significant increase of sICH among these patients,24 in comparison with nonwarfarin-treated patients. Unfortunately, our study could not lead to a certain conclusion regarding this controversy because there were only 2 patients who were on previous OAT and thrombolyzed afterward.
Conclusion Despite the fact that only 131 consecutive patients were analyzed and that there is a clear target for the future to reproduce this survey with a larger sample size, the results of our study suggest that stroke patients with AF do obtain benefit from thrombolysis. Therefore, the authors hope that this would be an extra tray on the scale in favor of the use of IVT in these patients.
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management of ischemic stroke and transient ischemic attack 2008. Cerebrovasc Dis 2008;25:457-507. van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604-607. Bendel R, Afifi A. Comparison of stopping rules in forward regression. J Am Stat Ass 1977;72:46-53. Henon H, Godefroy O, Leys D, et al. Early predictors of death and disability after acute cerebral ischemic event. Stroke 1995;26:392-398. Xian Y, Liang L, Smith E, et al. Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. JAMA 2012;307:2600-2608. Ruecker M, Matosevic B, Willeit P, et al. Subtherapeutic warfarin therapy entails an increased bleeding risk after stroke thrombolysis. Neurology 2012;79:31-38.
