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Outcomes of Treatment with Recombinant Tissue Plasminogen Activator in Patients Age 80 Years and Older Presenting with Acute Ischemic Stroke
From Summa Health System, Akron, OH.
Abstract
- Background: Ischemic stroke is a major cause of morbidity and mortality for patients ≥ 80 years old. The use of intravenous recombinant tissue plasminogen activator (tPA) in patients ≥ 80 years for treatment of ischemic stroke remains controversial.
- Objective: To examine outcomes in patients ≥ 80 years old who received tPA in our institution.
- Methods: This was a retrospective cohort study at a community-based certified acute stroke center. Individuals age ≥ 80 years evaluated emergently for acute neurologic changes consistent with ischemic stroke were included (n = 184). The comparison groups within this sample were patients who received tPA versus with those who did not because they came to the ED outside of the treatment window. Outcome measures included length of stay, symptomatic intracerebral hemorrhage (ICH), discharge disposition, and in-hospital death
- Results: 38 patients (20.7%) received tPA. 50 patients (27.2%) presented outside of treatment windows and were included in comparative analysis. There was no difference between groups in age (P = 0.26) or initial National Institute of Health Stroke Scale (P = 0.598). One patient (2.6%) who received tPA developed symptomatic ICH. Those receiving tPA were more likely to be discharged to acute rehabilitation hospitals (P = 0.012) and less likely to experience in hospital death (P = 0.048).
- Conclusion: At this institution, the use of tPA in patients ≥ 80 years old is not associated with increased mortality or risk of symptomatic ICH. Those who received tPA were more likely to be discharged to acute rehabilitation hospitals, suggesting greater potential for functional recovery.
Acute ischemic stroke is a major cause of morbidity and mortality in patients 80 years or older. Though less than 5% of the United States population is over the age of 80 [1], studies have shown that up to one-third of patients presenting with ischemic stroke are ≥ 80 years old [2] and among first-time strokes, a third occur in those ≥ 80 [3]. Older adults present with worse symptoms associated with ischemic stroke as measured by the National Institutes of Health Stroke Scale (NIHSS) compared with younger (< 80 years) counterparts [4]. Older patients are more likely to be discharged to a location other than home [5]. Older age is associated with higher hospital, 30-day, and 1-year mortality [3,5,6]. Patients ≥ 80 are significantly more likely to die in the hospital compared to younger patients, 11.7% to 23.6% vs 5.1%, respectively [3,7].
The Food and Drug Administration (FDA) approved the use of intravenous recombinant tissue plasminogen activator (tPA) in 1996 for the treatment of ischemic stroke [8]. Studies evaluating the safety and efficacy of tPA in ischemic stroke excluded or underrepresented patients ≥ 80 [8,9]. The use of tPA in those ≥ 80 has not been shown consistently to improve outcomes [6,10,11]. Post-hoc analysis of the National Institute of Neurologic Disorders and Stroke (NINDS) study did not show worse outcomes or harms to older adults treated with tPA [12]. Likewise, data from the International Stroke Treatment (IST-3) collaborative group show that treatment with tPA up to 6 hours from the onset of symptoms improves outcomes in the elderly [13]. Use of tPA in the oldest adults remains controversial due to perceived higher risk of symptomatic intracerebral hemorrhage (ICH). Published data suggest overall ICH risk of 4.3% to 6.4% across all age-groups [9,14,15].Studies have failed to demonstrate an increased risk in the oldest adults [4,10,16,17], though they may have higher mortality rates associated with ICH [15]. Despite this, trends suggest increasing use of tPA in those ≥ 80 over the past decade [2]. Along with primary data from NINDS [12] and IST-3 [13], a meta-analysis conducted in 2014 suggests that regardless of age, patients have improved outcomes with tPA [18].With the increasing age of the population, effective treatment of strokes in patients ≥ 80 will continue to be an important clinical and research endeavor.
This study evaluates the outcomes of clinical use of tPA for treatment of patients ≥ 80 years old who present to a community-based certified stroke center with ischemic stroke.
Methods
The study setting was a 540-bed acute care hospital that is a community-based certified stroke center. This study was deemed nonhuman subjects research by the institutional review board as the goal was to evaluate processes and outcomes of this institution’s stroke team in treating a subgroup of patients according to clinically accepted practice (quality improvement initiative). All patients presenting to the emergency department (ED) between 1 January 2011 and 30 November 2013 with the onset of stroke-like neurological deficits underwent evaluation and treatment by a neurologist and/or specially trained stroke team. This team consists of the attending neurologist, ED physician, resident physicians, advanced practice nurses, and ED staff nurses and emergency medicine technicians. Team members involved in the evaluation and treatment of these patients undergo routine clinical education and testing to ensure standardization. Patients undergo emergent evaluation including the National Institutes of Health Stroke Scale (NIHSS) and obtain brain imaging with computed tomography (CT).
Patients ≥ 80 years were identified among all those who presented to the ED with ischemic stroke. Patients were included if they were subsequently diagnosed with ischemic stroke or transient ischemic attacks (TIA). They were excluded from analysis if neurological changes were due to primary hemorrhagic stroke, intracranial hemorrhage, subarachnoid hemorrhage, seizure, conversion disorder, or metabolic derangements. They were also excluded from analysis if the acute ischemic stroke treatment included intra-arterial administration of tPA or endovascular revascularization.
Patient data collected included age, NIHSS at presentation to ED, time to presentation at ED, treatment with tPA, contraindications to tPA, discharge disposition, length of stay and in-hospital mortality. Raw NIHSS values were collected at the time of presentation. NIHSS were categorized into mild symptoms (NIHSS < 6), moderate symptoms (NIHSS 6–19), or severe symptoms (NIHSS ≥ 20). Clinical indications for receiving tPA include NIHSS > 4, focal neurological deficit onset < 3 hours (for those ≥ 80 years old), and no evidence of acute hemorrhage or acute infarct on CT. Contraindications include rapidly improving symptoms (repeat NIHSS < 4), active or history of intracranial hemorrhage, history of stroke or head trauma in past 3 months, gastrointestinal or genitourinary hemorrhage within 21 days, major surgery within 14 days, arterial puncture at a noncompressible site in past 7 days, treatment with anticoagulation with therapeutic indices, systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg and not responding to treatment, or platelet count < 100,000/mm3. Patients who were not eligible for tPA based on contraindications with the exception of being outside the treatment window (3 hours) were excluded from comparative analysis. Patient length of stay was rounded to nearest full day. Discharge disposition was categorized as home, acute rehabilitation hospital, skilled nursing facility, home or facility with hospice services, other hospital setting, or death.
Statistics were calculated using SPSS statistical software. Variables were reported as means and percentages. Group means were compared using t tests and differences in proportions were compared using the chi square test. Correlations were performed using Pearson’s correlation. A 2-tailed P < 0.05 was considered statistically significant.
Results
Discussion
Ischemic stroke remains a major cause of morbidity and mortality for very old patients. Though less than 5% of the United States population is over the age of 80 [1], at this community-based hospital 18% of those presenting to the ED with ischemic stroke were in this age-group. With a population of increasing age, more people in this age-group will present with ischemic stroke and need effective treatment to limit the associated morbidity and mortality. Being able to quickly and safely treat acute ischemic stroke may help very old adults maintain independence or prevent institutionalization. While the original studies demonstrating the effectiveness of tPA for acute ischemic stroke excluded or underrepresented those ≥ 80 years, retrospective analysis has not been conclusive regarding its use in very old patients [4–6,10,12,13].However, post-hoc analysis of NINDS and IST-3 data demonstrate efficacy and safety of treatment [12,13].
This study explored the use of tPA at a community-based certified stroke center. Similar to previous studies, it demonstrates the large proportion of patients presenting with acute neurological findings consistent with ischemic stroke are ≥ 80 years old [3,6]. Our incidence of acute ischemic stroke in the oldest patients may be slightly lower than reported elsewhere, which may reflect community differences, with higher rates of younger patients with multiple comorbidities presenting with stroke-like symptoms. Amongst this very old cohort, age was positively correlated with stroke severity. Mortality in patients ≥ 80 years old who present with acute ischemic stroke approaches 25%.
The majority of patients who did not receive tPA had documented contraindications to receiving the medication. The most common reason was rapidly improving symptoms with repeat NIHSS often ≤ 4. The second most common reason was presentation outside the treatment window of 3 hours. We compared those who either arrived too late to receive treatment with tPA or already had ischemic changes on CT to those who received tPA as this suggests the natural history of stroke progression and outcome without effective, early treatment. The outcomes at this institution support this trend. Very old patients who received tPA did not experience harm as evidenced by similar lengths of stay and rates of discharge to home. Also, rates of symptomatic ICH were lower than those reported in the literature. In fact, patients who received tPA were less likely to experience in-hospital death and more likely to be discharged to acute rehabilitation hospitals, suggesting more functional ability to tolerate aggressive recovery efforts.
Very few people who presented with acute ischemic stroke and were eligible for treatment with tPA failed to receive it. This suggests that despite the perceived increased risk to treating these patients with tPA, the specialized stroke team aggressively treats patients age ≥ 80 years who present with acute ischemic stroke. However, those who did not receive tPA were more likely to have presented with mild or severe strokes. This may suggest that treatment time frames are more strongly held, or that treatment teams are more likely to use time frames as a reason to not treat with tPA for patients with mild or severe strokes. Also, very few patients and families who were eligible to receive tPA declined treatment despite the associated risks. This suggests that patients and families are eager for aggressive treatment in attempt to prevent death or disability associated with ischemic stroke.
There are several limitations associated with this evaluation. First, this is a retrospective analysis of a single institution’s acute stroke procedures. Data was collected in an effort to evaluate the processes and outcomes of the specialized stroke team in evaluating and treating this very old cohort who present to a community-based hospital. It involved individualized clinical evaluation and decision making by multiple care providers who may offer different perspectives on the risk of treating patients ≥ 80 years old with tPA, which may result in selection bias. While comparing those who arrived outside treatment windows offers a comparison group who represents the natural course of untreated strokes, patient characteristics that prevented timely evaluation may also impact their outcomes including baseline mobility, care giving availability and underlying medical comorbidities. The similarity in mean presenting NIHSS scores of the two groups, however, argues against this possibility. Lastly, exclusion criteria to receiving tPA may represent intrinsic characteristics that impart higher risk of negative outcomes.
Conculsion
Although there have been no randomized controlled trials that evaluate the safety and efficacy of tPA in the treatment of acute ischemic stroke in very old patients, use at the community-based stroke center was not associated with worse outcomes including symptomatic ICH, hospital length of stay, and in-hospital mortality. In fact, there were trends towards better outcomes in older patients who received tPA, including a significant reduction in in-hospital mortality. This evaluation supports the benefits of using tPA to treat acute ischemic stroke as seen in prior randomized controlled trials that included the treatment of very old patients. Though ongoing research is needed, a growing body of evidence supports the use of tPA to treat acute ischemic stroke in patients ≥ 80 years.
Corresponding author: Jennifer C. Drost, DO, MPH, Summa Health System, 75 Arch St., Ste. G1, Akron, OH 44304, [email protected].
Financial disclosures: None.
Author contributions: Conception and design, JCD, SMB; analysis and interpretation of data, JCD, SMB; drafting of article, JCD; critical revision of the article, JCD, SMB; provision of study materials or patients, SMB; collection and assembly of data, JCD.
1. US Census Bureau. Annual estimates of the resident population for selected age groups by sex for the United States, States, Counties, and Puerto Rico Commonwealth and Municipios: April 1, 2010 to July 1, 2013. Accessed at www.census.gov/popest/index.html.
2. Fang MC, Cutler DM, Rosen AB. Trends in thrombolytic use for ischemic stroke in the United States. J Hosp Med 2010;5:406–9.
3. Marini C, Baldassarre M, Russo T, et al. Burden of first-ever ischemic stroke in the oldest old: evidence from a population-based study. Neurology 2004;62:77–81.
4. Sylaja PN, Cote R, Buchan AM, Hill MD. Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol Neurosurg Psychiatry 2006;77:826–9.
5. Heitsch LE, Panagos PD. Treating the elderly stroke patient: complications, controversies, and best care metrics. Clin Geriatr Med 2013;29:231–55.
6. Engelter ST, Bonati LH, Lyrer PA. Intravenous thrombolysis in stroke patients of > or = 80 versus < 80 years of age--a systematic review across cohort studies. Age Ageing 2006;35:572–580.
7. Forti P, Maioli F, Procaccianti G, et al. Independent predictors of ischemic stroke in the elderly: prospective data from a stroke unit. Neurology 2013;80:29–38.
8. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTischemic stroke, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768–74.
9. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–7.
10. Sung PS, Chen CH, Hsieh HC, et al. Outcome of acute ischemic stroke in very elderly patients: is intravenous thrombolysis beneficial? Eur Neurol 2011;66:110–6.
11. Saposnik G, Guzik AK, Reeves M, et al. Stroke prognostication using age and NIH Stroke Scale: SPAN-100. Neurology 2013;80:21–8.
12. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke 1997;28:2119–25.
13. Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352–63.
14. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke 1997;28:2109–18.
15. Bray BD, Campbell J, Hoffman A, et al. Stroke thrombolysis in England: an age stratified analysis of practice and outcome. Age Ageing 2013;42:240–5.
16. Kono S, Deguchi K, Morimoto N, et al. Intravenous thrombolysis with neuroprotective therapy by edaravone for ischemic stroke patients older than 80 years of age. J Stroke Cerebrovasc Dis 2013;22:1175–83.
17. Berrouschot J, Rother J, Glahn J, et al. Outcome and severe hemorrhagic complications of intravenous thrombolysis with tissue plasminogen activator in very old (> or =80 years) stroke patients. Stroke 2005;36:2421–5.
18. Emberson J, Lees KR, Lyden P, et al; Stroke Thrombolysis Trialists' Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929–35.
From Summa Health System, Akron, OH.
Abstract
- Background: Ischemic stroke is a major cause of morbidity and mortality for patients ≥ 80 years old. The use of intravenous recombinant tissue plasminogen activator (tPA) in patients ≥ 80 years for treatment of ischemic stroke remains controversial.
- Objective: To examine outcomes in patients ≥ 80 years old who received tPA in our institution.
- Methods: This was a retrospective cohort study at a community-based certified acute stroke center. Individuals age ≥ 80 years evaluated emergently for acute neurologic changes consistent with ischemic stroke were included (n = 184). The comparison groups within this sample were patients who received tPA versus with those who did not because they came to the ED outside of the treatment window. Outcome measures included length of stay, symptomatic intracerebral hemorrhage (ICH), discharge disposition, and in-hospital death
- Results: 38 patients (20.7%) received tPA. 50 patients (27.2%) presented outside of treatment windows and were included in comparative analysis. There was no difference between groups in age (P = 0.26) or initial National Institute of Health Stroke Scale (P = 0.598). One patient (2.6%) who received tPA developed symptomatic ICH. Those receiving tPA were more likely to be discharged to acute rehabilitation hospitals (P = 0.012) and less likely to experience in hospital death (P = 0.048).
- Conclusion: At this institution, the use of tPA in patients ≥ 80 years old is not associated with increased mortality or risk of symptomatic ICH. Those who received tPA were more likely to be discharged to acute rehabilitation hospitals, suggesting greater potential for functional recovery.
Acute ischemic stroke is a major cause of morbidity and mortality in patients 80 years or older. Though less than 5% of the United States population is over the age of 80 [1], studies have shown that up to one-third of patients presenting with ischemic stroke are ≥ 80 years old [2] and among first-time strokes, a third occur in those ≥ 80 [3]. Older adults present with worse symptoms associated with ischemic stroke as measured by the National Institutes of Health Stroke Scale (NIHSS) compared with younger (< 80 years) counterparts [4]. Older patients are more likely to be discharged to a location other than home [5]. Older age is associated with higher hospital, 30-day, and 1-year mortality [3,5,6]. Patients ≥ 80 are significantly more likely to die in the hospital compared to younger patients, 11.7% to 23.6% vs 5.1%, respectively [3,7].
The Food and Drug Administration (FDA) approved the use of intravenous recombinant tissue plasminogen activator (tPA) in 1996 for the treatment of ischemic stroke [8]. Studies evaluating the safety and efficacy of tPA in ischemic stroke excluded or underrepresented patients ≥ 80 [8,9]. The use of tPA in those ≥ 80 has not been shown consistently to improve outcomes [6,10,11]. Post-hoc analysis of the National Institute of Neurologic Disorders and Stroke (NINDS) study did not show worse outcomes or harms to older adults treated with tPA [12]. Likewise, data from the International Stroke Treatment (IST-3) collaborative group show that treatment with tPA up to 6 hours from the onset of symptoms improves outcomes in the elderly [13]. Use of tPA in the oldest adults remains controversial due to perceived higher risk of symptomatic intracerebral hemorrhage (ICH). Published data suggest overall ICH risk of 4.3% to 6.4% across all age-groups [9,14,15].Studies have failed to demonstrate an increased risk in the oldest adults [4,10,16,17], though they may have higher mortality rates associated with ICH [15]. Despite this, trends suggest increasing use of tPA in those ≥ 80 over the past decade [2]. Along with primary data from NINDS [12] and IST-3 [13], a meta-analysis conducted in 2014 suggests that regardless of age, patients have improved outcomes with tPA [18].With the increasing age of the population, effective treatment of strokes in patients ≥ 80 will continue to be an important clinical and research endeavor.
This study evaluates the outcomes of clinical use of tPA for treatment of patients ≥ 80 years old who present to a community-based certified stroke center with ischemic stroke.
Methods
The study setting was a 540-bed acute care hospital that is a community-based certified stroke center. This study was deemed nonhuman subjects research by the institutional review board as the goal was to evaluate processes and outcomes of this institution’s stroke team in treating a subgroup of patients according to clinically accepted practice (quality improvement initiative). All patients presenting to the emergency department (ED) between 1 January 2011 and 30 November 2013 with the onset of stroke-like neurological deficits underwent evaluation and treatment by a neurologist and/or specially trained stroke team. This team consists of the attending neurologist, ED physician, resident physicians, advanced practice nurses, and ED staff nurses and emergency medicine technicians. Team members involved in the evaluation and treatment of these patients undergo routine clinical education and testing to ensure standardization. Patients undergo emergent evaluation including the National Institutes of Health Stroke Scale (NIHSS) and obtain brain imaging with computed tomography (CT).
Patients ≥ 80 years were identified among all those who presented to the ED with ischemic stroke. Patients were included if they were subsequently diagnosed with ischemic stroke or transient ischemic attacks (TIA). They were excluded from analysis if neurological changes were due to primary hemorrhagic stroke, intracranial hemorrhage, subarachnoid hemorrhage, seizure, conversion disorder, or metabolic derangements. They were also excluded from analysis if the acute ischemic stroke treatment included intra-arterial administration of tPA or endovascular revascularization.
Patient data collected included age, NIHSS at presentation to ED, time to presentation at ED, treatment with tPA, contraindications to tPA, discharge disposition, length of stay and in-hospital mortality. Raw NIHSS values were collected at the time of presentation. NIHSS were categorized into mild symptoms (NIHSS < 6), moderate symptoms (NIHSS 6–19), or severe symptoms (NIHSS ≥ 20). Clinical indications for receiving tPA include NIHSS > 4, focal neurological deficit onset < 3 hours (for those ≥ 80 years old), and no evidence of acute hemorrhage or acute infarct on CT. Contraindications include rapidly improving symptoms (repeat NIHSS < 4), active or history of intracranial hemorrhage, history of stroke or head trauma in past 3 months, gastrointestinal or genitourinary hemorrhage within 21 days, major surgery within 14 days, arterial puncture at a noncompressible site in past 7 days, treatment with anticoagulation with therapeutic indices, systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg and not responding to treatment, or platelet count < 100,000/mm3. Patients who were not eligible for tPA based on contraindications with the exception of being outside the treatment window (3 hours) were excluded from comparative analysis. Patient length of stay was rounded to nearest full day. Discharge disposition was categorized as home, acute rehabilitation hospital, skilled nursing facility, home or facility with hospice services, other hospital setting, or death.
Statistics were calculated using SPSS statistical software. Variables were reported as means and percentages. Group means were compared using t tests and differences in proportions were compared using the chi square test. Correlations were performed using Pearson’s correlation. A 2-tailed P < 0.05 was considered statistically significant.
Results
Discussion
Ischemic stroke remains a major cause of morbidity and mortality for very old patients. Though less than 5% of the United States population is over the age of 80 [1], at this community-based hospital 18% of those presenting to the ED with ischemic stroke were in this age-group. With a population of increasing age, more people in this age-group will present with ischemic stroke and need effective treatment to limit the associated morbidity and mortality. Being able to quickly and safely treat acute ischemic stroke may help very old adults maintain independence or prevent institutionalization. While the original studies demonstrating the effectiveness of tPA for acute ischemic stroke excluded or underrepresented those ≥ 80 years, retrospective analysis has not been conclusive regarding its use in very old patients [4–6,10,12,13].However, post-hoc analysis of NINDS and IST-3 data demonstrate efficacy and safety of treatment [12,13].
This study explored the use of tPA at a community-based certified stroke center. Similar to previous studies, it demonstrates the large proportion of patients presenting with acute neurological findings consistent with ischemic stroke are ≥ 80 years old [3,6]. Our incidence of acute ischemic stroke in the oldest patients may be slightly lower than reported elsewhere, which may reflect community differences, with higher rates of younger patients with multiple comorbidities presenting with stroke-like symptoms. Amongst this very old cohort, age was positively correlated with stroke severity. Mortality in patients ≥ 80 years old who present with acute ischemic stroke approaches 25%.
The majority of patients who did not receive tPA had documented contraindications to receiving the medication. The most common reason was rapidly improving symptoms with repeat NIHSS often ≤ 4. The second most common reason was presentation outside the treatment window of 3 hours. We compared those who either arrived too late to receive treatment with tPA or already had ischemic changes on CT to those who received tPA as this suggests the natural history of stroke progression and outcome without effective, early treatment. The outcomes at this institution support this trend. Very old patients who received tPA did not experience harm as evidenced by similar lengths of stay and rates of discharge to home. Also, rates of symptomatic ICH were lower than those reported in the literature. In fact, patients who received tPA were less likely to experience in-hospital death and more likely to be discharged to acute rehabilitation hospitals, suggesting more functional ability to tolerate aggressive recovery efforts.
Very few people who presented with acute ischemic stroke and were eligible for treatment with tPA failed to receive it. This suggests that despite the perceived increased risk to treating these patients with tPA, the specialized stroke team aggressively treats patients age ≥ 80 years who present with acute ischemic stroke. However, those who did not receive tPA were more likely to have presented with mild or severe strokes. This may suggest that treatment time frames are more strongly held, or that treatment teams are more likely to use time frames as a reason to not treat with tPA for patients with mild or severe strokes. Also, very few patients and families who were eligible to receive tPA declined treatment despite the associated risks. This suggests that patients and families are eager for aggressive treatment in attempt to prevent death or disability associated with ischemic stroke.
There are several limitations associated with this evaluation. First, this is a retrospective analysis of a single institution’s acute stroke procedures. Data was collected in an effort to evaluate the processes and outcomes of the specialized stroke team in evaluating and treating this very old cohort who present to a community-based hospital. It involved individualized clinical evaluation and decision making by multiple care providers who may offer different perspectives on the risk of treating patients ≥ 80 years old with tPA, which may result in selection bias. While comparing those who arrived outside treatment windows offers a comparison group who represents the natural course of untreated strokes, patient characteristics that prevented timely evaluation may also impact their outcomes including baseline mobility, care giving availability and underlying medical comorbidities. The similarity in mean presenting NIHSS scores of the two groups, however, argues against this possibility. Lastly, exclusion criteria to receiving tPA may represent intrinsic characteristics that impart higher risk of negative outcomes.
Conculsion
Although there have been no randomized controlled trials that evaluate the safety and efficacy of tPA in the treatment of acute ischemic stroke in very old patients, use at the community-based stroke center was not associated with worse outcomes including symptomatic ICH, hospital length of stay, and in-hospital mortality. In fact, there were trends towards better outcomes in older patients who received tPA, including a significant reduction in in-hospital mortality. This evaluation supports the benefits of using tPA to treat acute ischemic stroke as seen in prior randomized controlled trials that included the treatment of very old patients. Though ongoing research is needed, a growing body of evidence supports the use of tPA to treat acute ischemic stroke in patients ≥ 80 years.
Corresponding author: Jennifer C. Drost, DO, MPH, Summa Health System, 75 Arch St., Ste. G1, Akron, OH 44304, [email protected].
Financial disclosures: None.
Author contributions: Conception and design, JCD, SMB; analysis and interpretation of data, JCD, SMB; drafting of article, JCD; critical revision of the article, JCD, SMB; provision of study materials or patients, SMB; collection and assembly of data, JCD.
From Summa Health System, Akron, OH.
Abstract
- Background: Ischemic stroke is a major cause of morbidity and mortality for patients ≥ 80 years old. The use of intravenous recombinant tissue plasminogen activator (tPA) in patients ≥ 80 years for treatment of ischemic stroke remains controversial.
- Objective: To examine outcomes in patients ≥ 80 years old who received tPA in our institution.
- Methods: This was a retrospective cohort study at a community-based certified acute stroke center. Individuals age ≥ 80 years evaluated emergently for acute neurologic changes consistent with ischemic stroke were included (n = 184). The comparison groups within this sample were patients who received tPA versus with those who did not because they came to the ED outside of the treatment window. Outcome measures included length of stay, symptomatic intracerebral hemorrhage (ICH), discharge disposition, and in-hospital death
- Results: 38 patients (20.7%) received tPA. 50 patients (27.2%) presented outside of treatment windows and were included in comparative analysis. There was no difference between groups in age (P = 0.26) or initial National Institute of Health Stroke Scale (P = 0.598). One patient (2.6%) who received tPA developed symptomatic ICH. Those receiving tPA were more likely to be discharged to acute rehabilitation hospitals (P = 0.012) and less likely to experience in hospital death (P = 0.048).
- Conclusion: At this institution, the use of tPA in patients ≥ 80 years old is not associated with increased mortality or risk of symptomatic ICH. Those who received tPA were more likely to be discharged to acute rehabilitation hospitals, suggesting greater potential for functional recovery.
Acute ischemic stroke is a major cause of morbidity and mortality in patients 80 years or older. Though less than 5% of the United States population is over the age of 80 [1], studies have shown that up to one-third of patients presenting with ischemic stroke are ≥ 80 years old [2] and among first-time strokes, a third occur in those ≥ 80 [3]. Older adults present with worse symptoms associated with ischemic stroke as measured by the National Institutes of Health Stroke Scale (NIHSS) compared with younger (< 80 years) counterparts [4]. Older patients are more likely to be discharged to a location other than home [5]. Older age is associated with higher hospital, 30-day, and 1-year mortality [3,5,6]. Patients ≥ 80 are significantly more likely to die in the hospital compared to younger patients, 11.7% to 23.6% vs 5.1%, respectively [3,7].
The Food and Drug Administration (FDA) approved the use of intravenous recombinant tissue plasminogen activator (tPA) in 1996 for the treatment of ischemic stroke [8]. Studies evaluating the safety and efficacy of tPA in ischemic stroke excluded or underrepresented patients ≥ 80 [8,9]. The use of tPA in those ≥ 80 has not been shown consistently to improve outcomes [6,10,11]. Post-hoc analysis of the National Institute of Neurologic Disorders and Stroke (NINDS) study did not show worse outcomes or harms to older adults treated with tPA [12]. Likewise, data from the International Stroke Treatment (IST-3) collaborative group show that treatment with tPA up to 6 hours from the onset of symptoms improves outcomes in the elderly [13]. Use of tPA in the oldest adults remains controversial due to perceived higher risk of symptomatic intracerebral hemorrhage (ICH). Published data suggest overall ICH risk of 4.3% to 6.4% across all age-groups [9,14,15].Studies have failed to demonstrate an increased risk in the oldest adults [4,10,16,17], though they may have higher mortality rates associated with ICH [15]. Despite this, trends suggest increasing use of tPA in those ≥ 80 over the past decade [2]. Along with primary data from NINDS [12] and IST-3 [13], a meta-analysis conducted in 2014 suggests that regardless of age, patients have improved outcomes with tPA [18].With the increasing age of the population, effective treatment of strokes in patients ≥ 80 will continue to be an important clinical and research endeavor.
This study evaluates the outcomes of clinical use of tPA for treatment of patients ≥ 80 years old who present to a community-based certified stroke center with ischemic stroke.
Methods
The study setting was a 540-bed acute care hospital that is a community-based certified stroke center. This study was deemed nonhuman subjects research by the institutional review board as the goal was to evaluate processes and outcomes of this institution’s stroke team in treating a subgroup of patients according to clinically accepted practice (quality improvement initiative). All patients presenting to the emergency department (ED) between 1 January 2011 and 30 November 2013 with the onset of stroke-like neurological deficits underwent evaluation and treatment by a neurologist and/or specially trained stroke team. This team consists of the attending neurologist, ED physician, resident physicians, advanced practice nurses, and ED staff nurses and emergency medicine technicians. Team members involved in the evaluation and treatment of these patients undergo routine clinical education and testing to ensure standardization. Patients undergo emergent evaluation including the National Institutes of Health Stroke Scale (NIHSS) and obtain brain imaging with computed tomography (CT).
Patients ≥ 80 years were identified among all those who presented to the ED with ischemic stroke. Patients were included if they were subsequently diagnosed with ischemic stroke or transient ischemic attacks (TIA). They were excluded from analysis if neurological changes were due to primary hemorrhagic stroke, intracranial hemorrhage, subarachnoid hemorrhage, seizure, conversion disorder, or metabolic derangements. They were also excluded from analysis if the acute ischemic stroke treatment included intra-arterial administration of tPA or endovascular revascularization.
Patient data collected included age, NIHSS at presentation to ED, time to presentation at ED, treatment with tPA, contraindications to tPA, discharge disposition, length of stay and in-hospital mortality. Raw NIHSS values were collected at the time of presentation. NIHSS were categorized into mild symptoms (NIHSS < 6), moderate symptoms (NIHSS 6–19), or severe symptoms (NIHSS ≥ 20). Clinical indications for receiving tPA include NIHSS > 4, focal neurological deficit onset < 3 hours (for those ≥ 80 years old), and no evidence of acute hemorrhage or acute infarct on CT. Contraindications include rapidly improving symptoms (repeat NIHSS < 4), active or history of intracranial hemorrhage, history of stroke or head trauma in past 3 months, gastrointestinal or genitourinary hemorrhage within 21 days, major surgery within 14 days, arterial puncture at a noncompressible site in past 7 days, treatment with anticoagulation with therapeutic indices, systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg and not responding to treatment, or platelet count < 100,000/mm3. Patients who were not eligible for tPA based on contraindications with the exception of being outside the treatment window (3 hours) were excluded from comparative analysis. Patient length of stay was rounded to nearest full day. Discharge disposition was categorized as home, acute rehabilitation hospital, skilled nursing facility, home or facility with hospice services, other hospital setting, or death.
Statistics were calculated using SPSS statistical software. Variables were reported as means and percentages. Group means were compared using t tests and differences in proportions were compared using the chi square test. Correlations were performed using Pearson’s correlation. A 2-tailed P < 0.05 was considered statistically significant.
Results
Discussion
Ischemic stroke remains a major cause of morbidity and mortality for very old patients. Though less than 5% of the United States population is over the age of 80 [1], at this community-based hospital 18% of those presenting to the ED with ischemic stroke were in this age-group. With a population of increasing age, more people in this age-group will present with ischemic stroke and need effective treatment to limit the associated morbidity and mortality. Being able to quickly and safely treat acute ischemic stroke may help very old adults maintain independence or prevent institutionalization. While the original studies demonstrating the effectiveness of tPA for acute ischemic stroke excluded or underrepresented those ≥ 80 years, retrospective analysis has not been conclusive regarding its use in very old patients [4–6,10,12,13].However, post-hoc analysis of NINDS and IST-3 data demonstrate efficacy and safety of treatment [12,13].
This study explored the use of tPA at a community-based certified stroke center. Similar to previous studies, it demonstrates the large proportion of patients presenting with acute neurological findings consistent with ischemic stroke are ≥ 80 years old [3,6]. Our incidence of acute ischemic stroke in the oldest patients may be slightly lower than reported elsewhere, which may reflect community differences, with higher rates of younger patients with multiple comorbidities presenting with stroke-like symptoms. Amongst this very old cohort, age was positively correlated with stroke severity. Mortality in patients ≥ 80 years old who present with acute ischemic stroke approaches 25%.
The majority of patients who did not receive tPA had documented contraindications to receiving the medication. The most common reason was rapidly improving symptoms with repeat NIHSS often ≤ 4. The second most common reason was presentation outside the treatment window of 3 hours. We compared those who either arrived too late to receive treatment with tPA or already had ischemic changes on CT to those who received tPA as this suggests the natural history of stroke progression and outcome without effective, early treatment. The outcomes at this institution support this trend. Very old patients who received tPA did not experience harm as evidenced by similar lengths of stay and rates of discharge to home. Also, rates of symptomatic ICH were lower than those reported in the literature. In fact, patients who received tPA were less likely to experience in-hospital death and more likely to be discharged to acute rehabilitation hospitals, suggesting more functional ability to tolerate aggressive recovery efforts.
Very few people who presented with acute ischemic stroke and were eligible for treatment with tPA failed to receive it. This suggests that despite the perceived increased risk to treating these patients with tPA, the specialized stroke team aggressively treats patients age ≥ 80 years who present with acute ischemic stroke. However, those who did not receive tPA were more likely to have presented with mild or severe strokes. This may suggest that treatment time frames are more strongly held, or that treatment teams are more likely to use time frames as a reason to not treat with tPA for patients with mild or severe strokes. Also, very few patients and families who were eligible to receive tPA declined treatment despite the associated risks. This suggests that patients and families are eager for aggressive treatment in attempt to prevent death or disability associated with ischemic stroke.
There are several limitations associated with this evaluation. First, this is a retrospective analysis of a single institution’s acute stroke procedures. Data was collected in an effort to evaluate the processes and outcomes of the specialized stroke team in evaluating and treating this very old cohort who present to a community-based hospital. It involved individualized clinical evaluation and decision making by multiple care providers who may offer different perspectives on the risk of treating patients ≥ 80 years old with tPA, which may result in selection bias. While comparing those who arrived outside treatment windows offers a comparison group who represents the natural course of untreated strokes, patient characteristics that prevented timely evaluation may also impact their outcomes including baseline mobility, care giving availability and underlying medical comorbidities. The similarity in mean presenting NIHSS scores of the two groups, however, argues against this possibility. Lastly, exclusion criteria to receiving tPA may represent intrinsic characteristics that impart higher risk of negative outcomes.
Conculsion
Although there have been no randomized controlled trials that evaluate the safety and efficacy of tPA in the treatment of acute ischemic stroke in very old patients, use at the community-based stroke center was not associated with worse outcomes including symptomatic ICH, hospital length of stay, and in-hospital mortality. In fact, there were trends towards better outcomes in older patients who received tPA, including a significant reduction in in-hospital mortality. This evaluation supports the benefits of using tPA to treat acute ischemic stroke as seen in prior randomized controlled trials that included the treatment of very old patients. Though ongoing research is needed, a growing body of evidence supports the use of tPA to treat acute ischemic stroke in patients ≥ 80 years.
Corresponding author: Jennifer C. Drost, DO, MPH, Summa Health System, 75 Arch St., Ste. G1, Akron, OH 44304, [email protected].
Financial disclosures: None.
Author contributions: Conception and design, JCD, SMB; analysis and interpretation of data, JCD, SMB; drafting of article, JCD; critical revision of the article, JCD, SMB; provision of study materials or patients, SMB; collection and assembly of data, JCD.
1. US Census Bureau. Annual estimates of the resident population for selected age groups by sex for the United States, States, Counties, and Puerto Rico Commonwealth and Municipios: April 1, 2010 to July 1, 2013. Accessed at www.census.gov/popest/index.html.
2. Fang MC, Cutler DM, Rosen AB. Trends in thrombolytic use for ischemic stroke in the United States. J Hosp Med 2010;5:406–9.
3. Marini C, Baldassarre M, Russo T, et al. Burden of first-ever ischemic stroke in the oldest old: evidence from a population-based study. Neurology 2004;62:77–81.
4. Sylaja PN, Cote R, Buchan AM, Hill MD. Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol Neurosurg Psychiatry 2006;77:826–9.
5. Heitsch LE, Panagos PD. Treating the elderly stroke patient: complications, controversies, and best care metrics. Clin Geriatr Med 2013;29:231–55.
6. Engelter ST, Bonati LH, Lyrer PA. Intravenous thrombolysis in stroke patients of > or = 80 versus < 80 years of age--a systematic review across cohort studies. Age Ageing 2006;35:572–580.
7. Forti P, Maioli F, Procaccianti G, et al. Independent predictors of ischemic stroke in the elderly: prospective data from a stroke unit. Neurology 2013;80:29–38.
8. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTischemic stroke, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768–74.
9. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–7.
10. Sung PS, Chen CH, Hsieh HC, et al. Outcome of acute ischemic stroke in very elderly patients: is intravenous thrombolysis beneficial? Eur Neurol 2011;66:110–6.
11. Saposnik G, Guzik AK, Reeves M, et al. Stroke prognostication using age and NIH Stroke Scale: SPAN-100. Neurology 2013;80:21–8.
12. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke 1997;28:2119–25.
13. Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352–63.
14. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke 1997;28:2109–18.
15. Bray BD, Campbell J, Hoffman A, et al. Stroke thrombolysis in England: an age stratified analysis of practice and outcome. Age Ageing 2013;42:240–5.
16. Kono S, Deguchi K, Morimoto N, et al. Intravenous thrombolysis with neuroprotective therapy by edaravone for ischemic stroke patients older than 80 years of age. J Stroke Cerebrovasc Dis 2013;22:1175–83.
17. Berrouschot J, Rother J, Glahn J, et al. Outcome and severe hemorrhagic complications of intravenous thrombolysis with tissue plasminogen activator in very old (> or =80 years) stroke patients. Stroke 2005;36:2421–5.
18. Emberson J, Lees KR, Lyden P, et al; Stroke Thrombolysis Trialists' Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929–35.
1. US Census Bureau. Annual estimates of the resident population for selected age groups by sex for the United States, States, Counties, and Puerto Rico Commonwealth and Municipios: April 1, 2010 to July 1, 2013. Accessed at www.census.gov/popest/index.html.
2. Fang MC, Cutler DM, Rosen AB. Trends in thrombolytic use for ischemic stroke in the United States. J Hosp Med 2010;5:406–9.
3. Marini C, Baldassarre M, Russo T, et al. Burden of first-ever ischemic stroke in the oldest old: evidence from a population-based study. Neurology 2004;62:77–81.
4. Sylaja PN, Cote R, Buchan AM, Hill MD. Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol Neurosurg Psychiatry 2006;77:826–9.
5. Heitsch LE, Panagos PD. Treating the elderly stroke patient: complications, controversies, and best care metrics. Clin Geriatr Med 2013;29:231–55.
6. Engelter ST, Bonati LH, Lyrer PA. Intravenous thrombolysis in stroke patients of > or = 80 versus < 80 years of age--a systematic review across cohort studies. Age Ageing 2006;35:572–580.
7. Forti P, Maioli F, Procaccianti G, et al. Independent predictors of ischemic stroke in the elderly: prospective data from a stroke unit. Neurology 2013;80:29–38.
8. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTischemic stroke, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768–74.
9. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–7.
10. Sung PS, Chen CH, Hsieh HC, et al. Outcome of acute ischemic stroke in very elderly patients: is intravenous thrombolysis beneficial? Eur Neurol 2011;66:110–6.
11. Saposnik G, Guzik AK, Reeves M, et al. Stroke prognostication using age and NIH Stroke Scale: SPAN-100. Neurology 2013;80:21–8.
12. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke 1997;28:2119–25.
13. Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352–63.
14. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke 1997;28:2109–18.
15. Bray BD, Campbell J, Hoffman A, et al. Stroke thrombolysis in England: an age stratified analysis of practice and outcome. Age Ageing 2013;42:240–5.
16. Kono S, Deguchi K, Morimoto N, et al. Intravenous thrombolysis with neuroprotective therapy by edaravone for ischemic stroke patients older than 80 years of age. J Stroke Cerebrovasc Dis 2013;22:1175–83.
17. Berrouschot J, Rother J, Glahn J, et al. Outcome and severe hemorrhagic complications of intravenous thrombolysis with tissue plasminogen activator in very old (> or =80 years) stroke patients. Stroke 2005;36:2421–5.
18. Emberson J, Lees KR, Lyden P, et al; Stroke Thrombolysis Trialists' Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929–35.