Comparison of acute nonthrombolytic and thrombolytic treatments in ischemic stroke patients 80 years or older

American Journal of Emergency Medicine (2012) 30, 158–164

www.elsevier.com/locate/ajem

Original Contribution

Comparison of acute nonthrombolytic and thrombolytic treatments in ischemic stroke patients 80 years or older☆ Haralabos Zacharatos DO, Ameer E. Hassan DO, Gabriela Vazquez PhD, Haitham M. Hussein MD, Gustavo J. Rodriguez MD, M. Fareed K. Suri MD, Kamakshi Lakshminarayan MD, PhD, Mustapha A. Ezzeddine MD, Adnan I. Qureshi MD ⁎ Zeenat Qureshi Stroke Research Center, University of Minnesota, Minneapolis, MN 55455, USA Received 3 August 2010; revised 10 November 2010; accepted 14 November 2010

Abstract Objectives: The aim of this study was to compare the clinical outcomes of acute ischemic stroke patients 80 years or older treated with intravenous recombinant tissue plasminogen activator (IV rt-PA), or endovascular intervention with or without IV rt-PA, or nonthrombolytic medical treatment. Methods: This study was a retrospective, nonrandomized, observational study of patients, admitted within 9 hours of symptom onset, at 3 academic, university-affiliated hospitals. The main outcome measures were neurologic improvement, defined by improvement in National Institutes of Health Stroke Scale score at 7 days or discharge of 4 or more, or achieving a score of 0; symptomatic and asymptomatic intracerebral hemorrhage; favorable outcome (discharge modified Rankin score 0-2); and in-hospital mortality. Results: A total of 44 patients received IV rt-PA, 46 received endovascular intervention with or without IV rt-PA, and 66 received nonthrombolytic medical treatment. IV rt-PA–treated patients had a significantly clinically higher chance of favorable outcome (odds ratio [OR], 5.6; 95% confidence interval [CI], 1.8-17.5), when compared with nonthrombolytic medical treatment. A significantly higher rate of neurologic improvement was observed among the IV rt-PA (7.2; 95% CI, 2.7-19.5) and endovascularly treated patients (5.8; 95% CI, 2-16.8) when compared with nonthrombolytic medical treatment. Conclusions: A prominently higher rate of neurologic improvement and favorable clinical outcome was observed among acute ischemic stroke patients 80 years or older treated with IV rt-PA or endovascular intervention when compared with nonthrombolytic medical treatment, supporting the use of acute thrombolytic therapies in this patient population when contraindications are not present. © 2012 Published by Elsevier Inc.

1. Introduction

☆ This research was not financially supported by any grant or external funding source. ⁎ Corresponding author. Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA. Tel.: +1 612 626 8221; fax: +1 612 625 7950. E-mail address: [email protected] (A.I. Qureshi).

0735-6757/$ – see front matter © 2012 Published by Elsevier Inc. doi:10.1016/j.ajem.2010.11.019

Persons 80 years or older are the fastest growing population in the United States, with an anticipated 3-fold increase expected by the year 2050 [1]. The incidence of stroke is also expected to increase with the increasing number of the older population [2-4]. Previous studies have demonstrated that patients 80 years or older (compared with those younger than 80 years) have a higher rate of

Ischemic stroke nonthrombolytic and thrombolytic treatments intracerebral hemorrhage (ICH) and poor clinical outcomes following treatment with intravenous recombinant tissue plasminogen activator (IV rt-PA) or endovascular intervention [5-7]. Several studies have excluded patients 80 years or older including the European Cooperative Acute Stroke Studies I, II, and III [8-10]; Alteplase Thrombolysis for Acute Non-Interventional Therapy in Ischemic Stroke [11] study; and the Interventional Management of Stroke I, II, and III trials [12-14]. However, the National Institute of Neurological Disorders and Stroke (NINDS) [15] trial randomized 42 patients 80 years or older to either IV rt-PA or placebo and demonstrated a small clinical benefit in regard to 3-month mortality rate and disability. We performed this study to compare the clinical outcomes between acute ischemic stroke patients 80 years or older treated with either IV rt-PA, endovascular intervention with or without IV rtPA, and nonthrombolytic medical treatment.

2. Methods A retrospective study was performed to identify all acute ischemic stroke patients 80 years or older admitted to any of 3 university-affiliated hospitals (University of Minnesota, Hennepin County, and University of Medicine and Dentistry of New Jersey Medical Centers) who received IV rt-PA and/ or endovascular intervention, from January 1, 2007, to July 31, 2009. All the patients, regardless of acute treatment used, who were admitted within 9 hours of symptom onset were identified using 2 sources: International Classification of Diseases, Ninth Revision, Clinical Modification codes 433437 as the primary discharge diagnoses and prospective databases of all acute ischemic stroke patients who received either IV rt-PA and/or endovascular intervention at all 3 institutions. A carefully maintained prospective database of acute ischemic stroke patients who received nonthrombolytic medical treatment was also maintained at the University of Minnesota and Hennepin County Medical Centers. We collected the following information from each eligible patient's hospital record: (1) age and sex and (2) cardiovascular risk factors present before onset of stroke, for example, hypertension, atrial fibrillation, coronary artery disease, diabetes mellitus, hyperlipidemia, and prior history of stroke or transient ischemic attack. The protocol for collecting data was reviewed and approved by the institutional review board at each institution as part of a standardized database. The results of the computed tomography (CT; noncontrast, angiography, and perfusion) imaging, cerebral angiography, and/or magnetic resonance imaging performed as part of the acute evaluation were recorded. All the patients selected for IV rt-PA presented to the hospital within 3 hours of symptom onset and did not have any contraindications for treatment [16]. The patients selected for endovascular intervention presented within 9 hours symptom onset, without any contraindications for treatment. The noncontrast cranial CT

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scan criteria required early ischemic changes, hypoattenuation, sulcal obliteration, and/or loss of gray white demarcation, not to involve an area greater than or equal to a third of the affected arterial distribution. Since 2007, patients presenting after 6 hours of symptom onset were additionally screened using qualitative CT perfusion (CT-P) imaging analysis. CT-P findings of preserved regional cerebral blood volume, decreased regional cerebral blood flow, and increased mean transit time were used to select patients for endovascular treatment. The patients were also excluded if the infarct burden was greater than or equal to one third (100 mL) of the vascular territory on qualitative analysis of CT-P, regional cerebral blood volume map. Our protocols for endovascular treatment have been previously described [17-19]. The outcome measures ascertained were asymptomatic and symptomatic ICH within 24 hours of treatment, and inhospital death. Each patient underwent a noncontrast cranial CT scan 24 hours after receiving any thrombolysis or in the event of any neurologic deterioration. Symptomatic ICH was defined as noncontrast CT scan–documented parenchymal ICH and related to neurologic deterioration (≥4 point worsening on National Institute of Health Stroke Scale [NIHSS] score compared with previous clinical assessment). Asymptomatic ICH was defined as noncontrast CT scan documented bleeding without any associated neurologic deterioration. The NIHSS score was used to assess the patients' neurologic deficits on admission and at 7 days or discharge consistent with previously published studies [6,20,21]. The NIHSS scores were estimated by the same NIHSS stroke scale–certified neurology resident, based on the recorded neurologic examinations. Neurologic improvement was defined by improvement in NIHSS score of 4 or higher or achieving a score of 0 at 7 days or discharge. Favorable functional outcome was defined by discharge modified Rankin scales (mRS) of 0 to 2. In-hospital mortality included patients who died after being placed on comfort care or secondary to a medical complication following treatment.

2.1. Statistical analysis We reported and compared the demographic characteristics, cardiovascular risk factors, severity of neurologic deficits graded by initial NIHSS score, and time interval between symptom onset and emergency department (ED) presentation of patients treated with either IV rt-PA, those treated with endovascular intervention with or without IV rtPA, or those treated with nonthrombolytic medical treatment. All data were descriptively presented using mean ± SD for continuous data and frequencies for categorical data. Comparison between groups was assessed using analysis of variance for continuous data and χ2 test for categorical data. We reported and compared the rate of favorable discharge outcome, neurologic improvement at 7 days or

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discharge, in-hospital mortality, and symptomatic and asymptomatic ICHs associated with three treatments. A multivariate logistic regression analysis was performed to determine the association between treatment modalities and various outcome measures after adjusting for potential confounding factors such as initial NIHSS score and age. P values are reported for overall difference (2-degree freedom, Wald χ2), and statistical significance was set to P b .05.

3. Results 3.1. Baseline demographic and clinical characteristics A total of 156 acute ischemic stroke patients 80 years or older were included (mean ± SD age, 86 ± 5 years; n = 64 [41%] were men). The proportion of patients according to time interval between symptom onset and ED arrival was as follows: 0 to 3 hours (n = 119, or 76%), 3 to 6 hours (n = 24, or 15%), and 6 to 9 hours (n = 13, or 8%). A total of 44 patients received IV rt-PA, 46 received endovascular intervention with or without IV rt-PA, and 66 received nonthrombolytic medical treatment. The patients' clinical characteristics are documented in Table 1. There was a significant difference across the 3 treatment groups with respect to time interval between symptom onset and ED arrival (P = .0002), mean age (P = .03), and mean NIHSS score at presentation (P b .0001). There were no other differences in the frequency or distribution of any other cardiovascular risk factors among various groups defined by treatment used (see Table 1). The severity of neurologic Table 1

deficits (mean NIHSS score) was higher and time interval between symptom onset and ED arrival shorter among patients who received either IV rt-PA treatment or endovascular intervention. Among the patients who received an endovascular intervention, there were 23 (48%) patients who received IV rt-PA. There were a total of 34 (74%) patients who presented within 3 hours of symptom onset, 9 (20%) patients who presented within 3 to 6 hours, and 3 (7%) patients who presented between 6 and 9 hours. A total of 17 (35%) of the patients also had a CT-P as part of their initial assessment. The following endovascular interventions were performed: intra-arterial thrombolytics in 33 (69%), mechanical thrombectomy in 24 (50%), angioplasty in 16 (33%), and stent placement in 6 (13%) patients. Multiple treatment strategies were used in selected patients. A total of 43 (94%) patients were treated within 6 hours of symptom onset.

3.2. NIHSS scores at 7 days or discharge and discharge mRS The unadjusted rates of favorable functional outcome and neurologic improvement for the 3 treatment groups are documented in Table 2. After adjusting for potential confounding factors, the IV rt-PA–treated patients had a significantly clinically higher chance of favorable outcome at discharge (5.6; 95% confidence interval [CI], 1.8-17.5), when compared with the patients who received nonthrombolytic medical treatment. Similarly, a significantly higher rate of neurologic improvement was also observed among both the IV rt-PA (7.2; 95% CI, 2.719.5) and the endovascularly treated groups (5.8; 95%

Demographic and clinical characteristics of patients presenting up to 9 hours after symptom onset

Variables

Overall

Nonthrombolytic medical treatment

IV rt-PA

Endovascular intervention ± IV rt-PA

No. of patients Mean age ± SD (y) Median age (range) (y) Men Diabetes mellitus Hypertension Hyperlipidemia Atrial fibrillation Coronary artery disease History of stroke/TIA Three or more risk factors NIHSS score at presentation Mean ± SD Median (range) Time to ED presentation (h) b3 3-6 6-9

156 86 ± 5 84 (80-102) 64 (41%) 28 (18%) 121 (78%) 59 (38%) 65 (42%) 43 (28%) 35 (22%) 61 (39%)

66 86 85 29 10 52 28 27 21 17 25

44 87 ± 6 85 (80-102) 13 (30%) 8 (19%) 36 (82%) 19 (43%) 13 (30%) 10 (23%) 10 (23%) 17 (39%)

46 84 ± 4 83 (80-97) 22 (48%) 10 (22%) 33 (72%) 12 (26%) 25 (54%) 12 (26%) 8 (17%) 19 (41%)

13 ± 8 12 (0-31)

8.2 ± 7.3 6 (0-31)

14.2 ± 6.9 14 (2-29)

17.5 ± 5.6 19 (3-29)

b.0001

119 (76%) 24 (15%) 13 (8%)

41 (62%) 15 (23%) 10 (15%)

44 (100%) – –

34 (74%) 9 (20%) 3 (7%)

.0002

TIA indicates transient ischemic attack.

±5 (80-98) (44%) (15%) (79%) (42%) (41%) (32%) (26%) (38%)

P

.03 .18 .67 .49 .15 .06 .56 .58 .93

Ischemic stroke nonthrombolytic and thrombolytic treatments Table 2

161

Unadjusted and adjusted clinical outcomes of patients presenting up to 9 hours after symptom onset Univariate analysis

Multivariate analysis a

Odds ratio (95% CI), P value ⁎

Odds ratio (95% CI), P value ⁎

24 (36%) 17 (39%) 8 (17%)

Reference 1.1 (0.5-2.4) 0.31 (0.12-8.1) P = .03

Reference 5.6 (1.8-17.5) 2.5 (0.63-9.6) P = .01

66 44 46

20 (30%) 27 (61%) 26 (57%)

Reference 3.7 (1.6-8.1) 2.7 (1.3-6) P = .003

Reference 7.2 (2.7-19.5) 5.8 (2-16.8) P = .0003

66 44 46

8 (12%) 7 (16%) 17 (37%)

Reference 1.4 (0.46-4.1) 4.25 (1.6-11) P = .006

Reference 0.64 (0.19-2.2) 2 (0.62-6.4) P = .14

66 44 46

6 (9%) 6 (14%) 10 (22%)

66 44 46

0 (0%) 1 (2%) 7 (15%)

Total patients

Proportion of patients

Favorable outcome (mRS 0-2) Nonthrombolytic medical treatment IV rt-PA Endovascular intervention ± IV rt-PA

66 44 46

NIHSS score improvement (≥4 or 0) at 7 d or discharge Nonthrombolytic medical treatment IV rt-PA Endovascular intervention ± IV rt-PA In-hospital mortality Nonthrombolytic medical treatment IV rt-PA Endovascular intervention ± IV rt-PA All ICH Nonthrombolytic medical treatment IV rt-PA Endovascular intervention ± IV rt-PA Symptomatic ICH Nonthrombolytic medical treatment IV rt-PA Endovascular intervention ± IV rt-PA a

Adjusted by initial NIHSS score and age. ⁎ P values are reported for overall difference, and statistical significance was set to P b .05.

CI, 2-16.8) when compared with the patients who received nonthrombolytic medical treatment, after adjustment for potential confounding factors.

3.3. ICH and in-hospital mortality rates There was no difference between the rates of in-hospital mortality among the 3 treatment groups. The rates of symptomatic and asymptomatic ICHs were higher among patients treated with either IV rt-PA and/or endovascular intervention when compared with nonthrombolytic medical treatment (see Table 2).

4. Discussion Acute ischemic stroke patients 80 years or older represent a growing population without a clearly defined role for IV rt-PA or endovascular intervention. We found that the initial NIHSS scores of patients who underwent an endovascular intervention with or without IV rt-PA were higher when compared with the IV rt-PA or the nonthrombolytic medical treatment group, indicating greater severity of neurologic deficits. After adjusting for initial NIHSS score and age, we found that patients 80 years or older with acute ischemic stroke who

received IV rt-PA had an approximately 6-fold higher odds of achieving a favorable discharge outcome compared with those who received nonthrombolytic medical treatment. The endovascularly treated patients also had higher odds (odds ratio of 2.5) of achieving favorable discharge outcome than those who received nonthrombolytic medical treatment. Similarly, patients treated with IV rt-PA or endovascular intervention were more likely to have a prominently higher chance of experiencing neurologic improvement at 7 days or discharge. Overall, there were no differences in hospital mortality between the treatment groups. Most retrospective and prospective acute ischemic stroke studies have compared the clinical outcomes and complication rates of patients 80 years or older with those observed in younger patients following treatment with IV rt-PA and concluded that the rates of poor outcome and death were higher among patients 80 years or older [22]. A meta-analysis of 6 studies, performed by Meseguer et al [23], of acute ischemic stroke patients treated with IV rt-PA within 3 hours of symptom onset found that there was a significantly greater incidence of unfavorable outcome at 3 months in patients 80 years or older in comparison with a younger cohort (72.7% vs 59.3%, P b .0001). The higher rate of poor outcomes among patients 80 years or older may be related to a limited amount of collaterals [24] and plasticity and higher rate of medical comorbidities [25]. It remains unclear whether the high rate of

162 disability or death precludes the benefit of acute thrombolytic treatment among patients 80 years or older. However, an analysis of the NINDS trial was unable to identify any patient group including those 80 years or older who should be excluded from IV rt-PA treatment [26]. The results of our IV rt-PA–treated group were more impressive than the results obtained for the patients who received an endovascular intervention. The rates of symptomatic ICH and in-hospital mortality observed among patients 80 years or older treated with IV rt-PA compare favorably with previously reported rates of symptomatic ICH and in-hospital mortality. Among 8 previously reported studies treating acute ischemic stroke patients 80 years or older with IV rt-PA within 3 hours of symptom onset, symptomatic ICH occurred between 2.6% and 13.6% and inhospital deaths ranged from 4.1% to 27.3% [22,23,27-33]. Meseguer et al [23] found that there was no significant difference between the incidence of symptomatic ICH between acute ischemic stroke patients 80 years or older and patients younger than 80 years treated with IV rt-PA within 3 hours of symptom onset (6.1% vs 5.2%, P = .25). Among patients 80 years or older treated with an endovascular intervention, we observed a relatively high rate of symptomatic ICH and in-hospital mortality: 15% for ICH and 37% for in-hospital mortality. The increased rate of ICH in acute ischemic stroke patients 80 years or older who underwent endovascular treatment with or without IV rt-PA may be due to rapid blood-brain barrier disruption associated with ischemia and inadequate collaterals [7], presence of amyloid angiopathy [34], and higher rates of post treatment hypertension [35]. The additional intra-arterial thrombolytics given to patients who already received IV rt-PA may also increase the risk of posttreatment procedure–related ICH because of delayed clearance of IV rt-PA in older patients [36]. It remains unclear whether arterial injury secondary to mechanical disruption of the clot further contributes to the risk of ICH. With respect to our patients who received an endovascular intervention, our in-hospital mortality rate was similar to the 54% rate reported by a meta-analysis of 4 prospective studies of patients 80 years or older who received either a combination of intravenous thrombolysis and endovascular intervention or endovascular intervention alone [7]. Limited reported literature is available regarding the in-hospital mortality of patients 80 years or older treated with the combination of intravenous thrombolysis and endovascular intervention [6,22]. In a report of 62 acute ischemic stroke patients, Flaherty et al [37] treated 8 patients 80 years or older with a combination of intravenous and endovascular therapy, and they reported 5 (63%) in-hospital deaths [37]. It remains unclear whether the higher rates of symptomatic ICH and death associated with endovascular intervention support preferential use of IV rt-PA in this patient population. Higher complications associated with endovascular interventions among patients 80 years or older

H. Zacharatos et al. have been reported among those undergoing carotid or intracranial angioplasty and/or stent placement [7,38-40].

4.1. Study Limitations The first limitation of this study is the retrospective design, which partly precludes standardized patient selection criteria and outcome ascertainment. The number of patients in each subgroup was too small for us to ascertain any differential rates of outcomes with various endovascular interventions. The analysis was also underpowered to compare the rates of asymptomatic and symptomatic ICHs between the 3 treatment groups because of the unbalanced distribution of potential confounding factors such as initial NIHSS score. An attempt was made to minimize confounding bias, across the 3 treatment groups, through the adjustment for initial NIHSS score and age. Time interval between symptom onset and ED arrival was not the same across all treatment groups. Patients who arrived early were eligible for IV rt-PA and/or endovascular treatment giving them an opportunity for clinical improvement. This confounding bias was not possible to adjust in the multivariable model because the time distribution did not intersect between groups. Also, the nonthrombolytic medically treated patients were all identified from 2 of the 3 medical centers. During the comparison with other published symptomatic ICH rates, a post hoc analysis was not performed according to the definitions used in the other trials. Prestroke mRS or NIHSS scores were not documented consistently, potentially undermining the benefit of treatment among patients with prestroke neurologic deficits who were already functionally limited with a poor mRS (3-5). Unfortunately, we also did not have 3-month functional outcomes or mortality rates. The NIHSS score was documented for 7 days or discharge to capture any delayed neurologic improvement. Broderick et al [41] performed an exploratory study designed to determine which binary end points would consistently require the fewest number of patients to detect a significantly beneficial effect of IV rt-PA among the NINDS IV rt-PA stroke trial, and found that the most powerful measure of the effectiveness of IV rt-PA during the first 3 months after an ischemic stroke was a given level or amount of change in the NIHSS score during the first 24 hours after start of treatment. Similarly, Broderick et al [41] found that the NIHSS scores at 7 to 10 days following treatment was also one of the most sensitive measures for detecting differences in longer-term outcome. The prognostic value of early differential benefit observed in the NINDS IV rt-PA trial supports the conclusions of our observational study.

5. Conclusion A prominently higher rate of favorable clinical outcome and neurologic improvement was observed among acute ischemic stroke patients 80 years or older treated with IV rt-

Ischemic stroke nonthrombolytic and thrombolytic treatments PA or endovascular intervention when compared with nonthrombolytic medical treatment in this observational study, supporting the use of acute thrombolytic therapies in this patient population when contraindications are not present. A larger randomized prospective study is recommended to further study the benefits of acute thrombolytic therapy in this patient population.

[12]

[13] [14]

[15]

Acknowledgment All the authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All the authors had equal responsibility with respect to the synthesis of ideas and writing of this study.

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