CNS Drugs (2014) 28:1035–1045 DOI 10.1007/s40263-014-0204-0

REVIEW ARTICLE

Alteplase in Acute Ischemic Stroke: Putting the Guidelines into Practice Nandakumar Nagaraja • Harold P. Adams Jr.

Published online: 19 October 2014  Springer International Publishing Switzerland 2014

Abstract Intravenous recombinant tissue plasminogen activator (rt-PA or alteplase) is the only approved medical intervention for treatment of acute ischemic stroke within the first hours of symptom onset. In this article, we review the preliminary studies of rt-PA in acute ischemic stroke that led to US FDA approval of its use within 3 h of symptom onset. The studies on rt-PA for use beyond 3 h of symptom onset and future reperfusion therapies are discussed. Overviews of the clinical presentation and treatment of acute ischemic stroke and stroke systems of care are described.

Key Points While intravenous rt-PA has received US FDA approval for treatment of acute ischemic stroke within 3 h of symptom onset, guidelines recommend that the agent be administered to carefully selected patients up to 4.5 h after stroke. The benefits outweigh the risk when rt-PA is administered to patients who meet the inclusion and exclusion criteria. Prompt early recognition, evaluation, and treatment of acute ischemic stroke is necessary to minimize disability.

N. Nagaraja
H. P. Adams Jr. (&) Division of Cerebrovascular Diseases, Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, 2148 RCP, Iowa City, IA 52242, USA e-mail: [email protected]

1 Introduction Since 1996, intravenous recombinant tissue plasminogen activator (rt-PA or alteplase) has been the only approved acute medical intervention available for patients presenting within the first hours of onset of acute ischemic stroke. In this article, we review the preliminary studies that led to the publication of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke study in 1995, with subsequent approval of the drug by the US FDA in 1996. The studies on rt-PA for use beyond 3 h of symptom onset and future reperfusion therapies are also discussed. Practical tips for recognizing the symptoms and signs of stroke by the emergency department physicians and the immediate evaluation needed for administering the intravenous rt-PA based on current recommendations by the American Heart Association (AHA)/American Stroke Association (ASA) are described.

2 Studies Leading to the US FDA Approval of Recombinant Tissue Plasminogen Activator (rt-PA) for Use in 0–3 h of Symptom Onset Two pilot studies known as ‘Urgent Therapy for Stroke’, were conducted to evaluate the safety of intravenous rt-PA within 180 min of onset of acute ischemic stroke [1, 2]. The Urgent Therapy for Stroke Part I pilot study was a dose-escalation safety study of rt-PA administered within 90 min of stroke onset [1]. The inclusion and exclusion criteria are listed in Table 1. The dose tiers included 0.35, 0.60, 0.85, 0.95, or 1.08 mg/kg body weight, with a maximum total dose of 100 mg. The data safety and monitoring committee reviewed the cases treated in each dose group and made

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Table 1 Inclusion and exclusion criteria for Urgent Therapy For Stroke and National Institute of Neurological Disorders and Stroke rt-PA stroke studies [1–3] UTS I

UTS II

NINDS

Inclusion criteria 1. Age 18–80 years

4

4

4

2. Age [80 years

·

·

4

3. Diagnosis of AIS with measurable deficit on NIHSS

4

4

4

4. Able to start rt-PA within 90 min of stroke onset

4

·

4

5. Able to start rt-PA 91–180 min of stroke onset

·

4

4

Exclusion criteria 1. Onset of symptoms on awakening from sleep

4

4

·

2. Intracranial hemorrhage on pre-treatment CT head

4

4

4

3. Clinical presentation of SAH even if CT head is normal

4

4

4

4. Pregnancy

4

4

4

5. PT [15 s

4

4

4

6. Abnormal PTT

4

4

4

7. Platelets \100,000

4

4

4

8. Arterial puncture of a non-compressible site within 7 days

4

4

4

9. Significant surgery within the previous 14 days

4

4

4

10. Gastrointestinal or urinary tract hemorrhage within 21 days

4

4

4

11. Trauma in past 14 days or lumbar puncture within 7 days

4

4

·

12. Serious head trauma in the past 3 months

·

·

4

13. Previous cerebral infarction within 3 months

4

4

4

14. Previous cerebral hemorrhage within 3 months

4

4

·

15. Any history of intracranial hemorrhage in the past 16. Pre-treatment SBP [200 mmHg or DBP [120 mmHg

· 4

· 4

4 ·

17. Pre-treatment SBP [185 mmHg or DBP [115 mmHg

·

·

4

18. Blood glucose \50 or [400 mg/dl

·

·

4

19. Rapidly improving or minor symptoms

·

·

4

20. Sensory loss or ataxia alone

4

4

·

21. Seizure at onset of stroke

·

·

4

22. Inability to obtain informed consent

4

4

4

23. Other serious medical illness that might interfere with the study

4

4

·

24. MAP [133 mmHg

4

4

·

25. Transmural myocardial infarction with clinical pericarditis

4

4

·

AIS acute ischemic stroke, CT computed tomography, DBP diastolic blood pressure, MAP mean arterial pressure, NIHSS National Institutes of Health Stroke Scale, NINDS National Institute of Neurological Disorders and Stroke, PT prothrombin time, PTT partial thromboplastin time, rtPA recombinant tissue plasminogen activator, SAH subarachnoid hemorrhage, SBP systolic blood pressure, UTS Urgent Therapy for Stroke study #24 and #25 were included as contraindications during the course of the UTS Part I study

a consensus decision for proceeding to the next higher dose. The stopping threshold was the occurrence of two intracerebral hemorrhage (ICH) cases in the first six consecutively treated patients in a dose tier. The safety endpoint was occurrence of ICH, hemorrhagic transformation without ICH, systemic hemorrhage, and death resulting from any hemorrhagic complications. A total of 74 patients were treated with rt-PA, and three of these patients subsequently had a diagnosis of transient ischemic attack. Three of the 26 patients (11 %) who received an rt-PA dose of C0.95 mg/kg developed ICH

within 24 h. No ICH occurred in doses \0.95 mg/kg. Two major systemic hemorrhagic complications also occurred. One patient who developed sub-pericardial hemorrhage with pericardial tamponade within 1 h of completion of rtPA infusion had experienced acute myocardial infarction in the previous 5 days. The other patient who developed retroperitoneal hematoma at 24 h had a transfemoral cerebral angiogram prior to intravenous rt-PA and was also started on intravenous heparin 12 h after rt-PA infusion. Both of these patients had received an rt-PA dose of 0.95 mg/kg.

Alteplase in Acute Ischemic Stroke

The Urgent Therapy for Stroke Part II pilot study was also a dose-escalation study of rt-PA at 0.6, 0.85, or 0.95 mg/kg; it was administered at 91–180 min of stroke onset [2]. Most of the inclusion and exclusion criteria were the same as for Part I. It had additional exclusion criteria of mean arterial pressure (MAP) [133 mmHg, recent transmural myocardial infarction or clinical pericarditis. Ten percent of the total rt-PA dose was administered as bolus. A total of 20 patients were enrolled and two (10 %) developed fatal ICH, one at 0.85 mg/kg and the other at 0.95 mg/kg rt-PA dose. This study was stopped early due to increased hemorrhagic complications noted at C0.95 mg/kg in Part I of the study. The results of the Urgent Therapy for Stroke pilot studies led to the development of the larger phase III randomized, placebo-controlled trial of intravenous rt-PA in acute ischemic stroke by the NINDS rt-PA study group [3]. It was also clear from these studies that a dose of \0.95 mg/kg t-PA was probably safe. The NINDS rt-PA study was conducted in two parts. Part I evaluated for immediate benefit from rt-PA assessed by neurological improvement at 24 h. The primary outcome was early improvement, defined as complete resolution of neurological symptoms or improvement in National Institutes of Health Stroke Scale (NIHSS) C4 points at 24 h after the onset of stroke. Part II assessed recovery from stroke at 3 months as a measure of sustained benefit from rt-PA. The primary outcome of part II of the study was recovery from stroke at 3 months assessed by the Barthel Index, the modified Rankin Scale (mRS), the NIHSS, and the Glasgow Outcome Scale (GOS). A score of 95 or 100 on the Barthel Index, B1 on the NIHSS, B1 on the mRS, and 1 on the GOS were considered favorable outcomes. A global test statistic was used to combine all the outcome measures at 3 months. Secondary outcomes were recovery at 3 months for part I and early neurological improvement at 24 h for part II of the study. Symptomatic intracranial hemorrhage was defined as any neurological worsening on the NIHSS compared with baseline, with evidence of blood on computed tomography (CT) head scan performed within 36 h of rt-PA administration. The entry criteria for the NINDS rt-PA study are listed in Table 1. The trial enrolled 624 patients who were randomized to an rt-PA or a placebo group. The rt-PA dose was 0.9 mg/kg body weight, with a maximum of 90 mg; 10 % administered as bolus over 1–2 min to provide immediate thrombolytic activity and the remaining as infusion over 60 min. No antiplatelets or anticoagulants were administered in the first 24 h after rt-PA administration. In both part I and part II, patients were further stratified for treatment with rt-PA or placebo based on time from symptom onset to drug administration -0 to 90 or 91 to 180 min.

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No significant difference was observed between the rtPA and placebo groups in part I of the study in terms of the primary outcome—early neurological improvement at 24 h. It was true for patients stratified by time 0–90, 91–180, or combined 0–180 min. The secondary outcome for part II—early neurological improvement at 24 h—was significant for patients treated in 0–90 min but not for those treated in 91–180 min or the combined 0–180 min. When early neurological improvement was assessed for the combined part I and part II of the study, it was significant only for the 0–90 min group and a trend for the combined 0–180 min group but not for the 91–180 min group. A significant difference was observed in the primary outcome for part II. An absolute difference of 11 % occurred in the NIHSS, 12 % in the Barthel Index and the GOS, and 13 % in mRS between the rt-PA and placebo group. The odds ratio for favorable outcome by global test statistic was 1.7 for treatment with rt-PA. This significant difference for treatment with rt-PA was also seen in the secondary outcome measures for the part I study population and when both part I and II were combined and evaluated for treatment at 0–90 and 91–180 min from stroke onset. The positive results were not affected when patients were classified by stroke subtype—small vessel disease, large vessel disease, or cardioembolism [3]. No significant difference was observed in mortality at 3 months between the rt-PA (17 %) and the placebo (21 %) group. However, a tenfold increase was observed in symptomatic intracranial hemorrhage within 36 h of treatment with rt-PA (6.4 %) compared with the placebo group (0.6 %), and half of these patients died due to the hemorrhage. The risk of hemorrhage was higher with an increase in stroke severity and advanced age. This risk was 20 % in patients with baseline NIHSS [22 and age [77 years. No difference was observed in asymptomatic hemorrhages between the rt-PA and placebo groups. Thus, treatment with intravenous rt-PA within 3 h of onset of stroke showed benefit with functional recovery when evaluated at 3 months, regardless of the stroke subtype, and the benefit outweighed the risk of early hemorrhage in small group of patients, with no difference in mortality at 3 months. A placebo-controlled study, the ECASS I (European Cooperative Acute Stroke Study I), reported no benefit from treatment with intravenous rt-PA at 1.1 mg/kg given within 6 h of symptom onset [4]. The ECASS I study recruited 620 patients aged 18–80 years with moderate-tosevere hemispheric stroke. Eligible patients had negative or only minor signs of infarct on initial CT head scan. Patients with improving symptoms, minor symptoms with Scandinavian Stroke Scale (SSS) score [50 points, and most severe hemisphere strokes with moderate-to-severe hemiparesis, sensory changes, non-fluent aphasia, dysarthria, or

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hemianopia were excluded. The SSS scores ranged from 0 to 58, with 58 being normal with no neurological deficits. Mean time from onset to treatment was 4.4 h, with 15 % treated within the first 3 h of stroke onset. The primary endpoint in ECASS I was a difference in the Barthel Index of 15 points between rt-PA and placebo groups and difference in mRS of one grade at 90 days. In the intention-to-treat analysis, there was no difference in the primary endpoint between the rt-PA and placebo groups. However, in the target population with the exclusion of patients with protocol violations, significant improvement with rt-PA was found with mRS but not with the Barthel Index at 90 days. The secondary endpoints of SSS score at 90 days and mortality at 30 days did not differ between the two groups. However, the 90-day mortality was significantly higher in the rt-PA group (22 %) than in the placebo group (15.8 %). The combined score of Barthel Index/mRS was significant in the intention-to-treat analysis and in the target population. However, 48.4 % of the patients who enrolled with the presence of major early infarct signs on CT head (a protocol violation) and treated with rt-PA died. There were no significant differences in the ICH. However, hemorrhagic infarction, defined as petechial or confluence of petechiae, was higher in the placebo group (30.3 %) than in the rt-PA group (23 %). Parenchymal hematomas, defined as blood clot with space occupying effect, were higher in the rt-PA group (19.8 vs. 6.5 % in placebo). There seemed to be some benefit of better functional outcome in the target population for the rt-PA group. However, due to an increase in mortality at 90 days and higher parenchymal hematomas in the rt-PA group, the study concluded that the risk of treatment with rt-PA was greater than the benefit in this patient population. In June 1996, the Peripheral and Central Nervous System Advisory Committee of the Federal FDA reviewed the results of the dose-escalation pilot studies, NINDS rt-PA study, and ECASS I and recommended the approval of the use of rt-PA for acute ischemic stroke within 3 h from symptom onset after excluding intracranial hemorrhage with a CT scan. The FDA approval of rt-PA was a major breakthrough for patients with stroke because no acute stroke treatments had previously existed. Although the rt-PA was restricted to only a small group of stroke patients that met the criteria in the NINDS study, it was a promising treatment for good functional recovery with a small but serious risk of hemorrhagic complications. However, not all physicians accepted the recommendation to use rt-PA [5, 6]. Many were fearful about the risk of hemorrhagic complications. Neurologists who were largely used to the non-emergent outpatient practice setting now needed to respond to acute stroke calls from the emergency department. However,

N. Nagaraja, H. P. Adams Jr.

with time, there was a growing recognition of the therapeutic efficacy of rt-PA in acute ischemic stroke patients within 3 h of symptom onset, and several retrospective analyses of stroke registries and trials consistently proved its efficacy when administered without deviation from the NINDS rt-PA study criteria.

3 Studies Published After FDA Approval of rt-PA for Use in 0–3 h of Symptom Onset ECASS II was conducted in Europe and Australia between October 1996 and January 1998 and randomized patients to rt-PA 0.9 mg/kg or placebo within 6 h of symptom onset [7]. Compared with the ECASS I study, a dose similar to the NINDS rt-PA study was used. Investigators also had strict criteria for blood pressure control and CT eligibility to avoid the protocol deviations noted in ECASS I. The primary endpoint was mRS of 0 or 1 at 90 days. No significant difference between the two groups was observed for the primary endpoint (40.3 % rt-PA vs. 36.6 % placebo). The results were unchanged when stratified by time 0–3 and 3–6 h. The ATLANTIS (Alteplase Thrombolysis for Acute Non-Interventional Therapy in Ischemic Stroke) study in North America initially randomized patients to rt-PA 0.9 mg/kg or placebo within 6 h of symptom onset [8]. The study was initiated in August 1991. However, due to concerns raised by the data safety and monitoring committee, treatment in the 5- to 6-h time window was halted in October 1993. This group was known as ATLANTIS Part A. The study was restarted in December 1993 as part B, with randomization restricted to a time window of only 0–5 h. However, after the results of the NINDS rt-PA study, the ATLANTIS Part B study was further modified to a time window of 3–5 h in February 1996. The agent was not found to be beneficial for treatment of acute ischemic stroke patients in the 3- to 5-h time window [9]. Another analysis of patients randomized within 3 h of symptom onset in the ATLANTIS study found a significant favorable outcome at 90 days (NIHSS B1) with the rt-PA group compared with the placebo group, supporting the NINDS rt-PA data [10]. The NINDS rt-PA stroke group further analyzed the study data and found that earlier treatment of stroke was associated with better outcomes, even within the first 3 h of symptom onset [11]. The odds ratio for favorable outcome at 3 months adjusted for the NIHSS was 2.11 for treatment in 0–90 min from symptom onset; it dropped to 1.69 for treatment in 91–180 min from symptom onset. These results were further replicated in the pooled analysis of the ATLANTIS, ECASS, and NINDS rt-PA stroke trials, with the limitations of a higher dose in the ECASS I, slightly

Alteplase in Acute Ischemic Stroke

different exclusion criteria, and differences in outcome measures in these studies [12]. The 3-month favorable outcome was defined as NIHSS B1, mRS B1, and Barthel Index 95 or 100. The odds ratio for favorable outcome at 3 months was 2.8, 1.6, 1.4, and 1.2 for treatment of patients with rt-PA at 0–90, 91–180, 181–270, and 271–360 min from stroke onset, respectively. The parenchymal hematoma type II, defined as [30 % of the infarct with mass effect, was higher in the rt-PA group (5.9 %) than in the placebo group (1.1 %). The occurrence of parenchymal hematoma was not associated with stroke onset to treatment time but was associated with age and baseline severity of stroke. Further updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial) showed similar 3-month favorable outcome rates at each of the above time points from symptom onset [13]. These studies clearly indicated that early treatment with rt-PA was successful. The current ‘Target Stroke’ initiative by the AHA/ASA aims to treat at least 50 % of ischemic stroke patients with intravenous rt-PA within 60 min of arrival to the emergency department. Treating acute ischemic stroke patients within 60 min of arrival to the hospital has been associated with decreases in intracranial hemorrhage and in-hospital mortality, and an increase in the number of patients discharged home [14]. The ECASS III trial was initiated, with the encouraging results of the pooled analysis indicating favorable outcomes at 3 months with an odds ratio of 1.4 for treatment with intravenous rt-PA in the 3- to 4.5-h time window without an increase in the risk of parenchymal hematoma [15]. The study inclusion and exclusion criteria were similar to those of the NINDS rt-PA trial, except for the following exclusions: patients aged over 80 years, severe strokes with NIHSS [25, treatment with any oral anticoagulation regardless of international normalized ratio (INR) value, and those with history of stroke and diabetes mellitus. The trial enrolled 821 patients who were randomized to placebo or rt-PA 0.9 mg/kg. A significant difference was observed in the primary outcome of mRS B1 at 90 days, favoring treatment with rtPA (52.4 %) versus placebo (45.2 %), with absolute difference of 7.2 %. The odds ratio for favorable outcome for treatment with rt-PA in 3–4.5 h was 1.34, similar to that observed in the pooled analysis. The secondary outcome was a global outcome measure that combined NIHSS B1, mRS B1, Barthel Index C95, and GOS of 1 at 90 days. The global odds ratio for favorable outcome at 90 days was 1.28. No difference in death was observed between rt-PA (7.7 %) and placebo groups (8.4 %). However, rates of intracranial hemorrhage in the rt-PA group (27 %) were higher than in the placebo group (17.6 %). Symptomatic intracranial hemorrhage, defined as neurologic

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deterioration with increase in NIHSS C4 points or more than the value at baseline or the lowest value in the first 7 days, or any hemorrhage leading to death, was higher in the rt-PA (2.4 %) than in the placebo group (0.2 %). Symptomatic intracranial hemorrhage per NINDS rt-PA study criteria was 7.9 % for rt-PA and 3.5 % for placebo. This study showed some modest benefit with rt-PA in the 3- to 4.5-h time window, without increase in mortality; the hemorrhage rates were similar to those of the previous NINDS study. The results of this study led to the modification of the AHA/ASA treatment guidelines to include treatment of patients with acute ischemic stroke in the 3- to 4.5-h time window if they met additional exclusion criteria as in the study [16]. The European Medicines Agency approved the use of intravenous rt-PA in the extended time window of 3–4.5 h from symptom onset; however, the FDA did not approve its use in this time window [17]; the reasons for this are not clear. However, the widespread use of rt-PA in the 3- to 4.5-h time window means it is unlikely that another trial will be developed to evaluate its efficacy in this time window. The IST-3 (International Stroke Trial-3) evaluated the efficacy of rt-PA versus placebo in acute ischemic stroke 0–6 h from symptom onset in patients who did not exactly meet the criteria for rt-PA in Europe, particularly elderly patients aged [80 years and those with high NIHSS scores [18]. The primary outcome was proportion of patients alive and independent, measured as 0–2 on the Oxford Handicap Scale (OHS) at 6 months [19]. The OHS is quite similar to the mRS. Among 3,035 patients enrolled, 53 % were older than 80 years and about 45 % were treated 4.5–6 h from symptom onset. No difference was observed in the primary outcome of OHS 0–2 at 6 months between the rt-PA (37 %) and placebo (35 %) groups. However, a secondary ordinal analysis showed a shift in the OHS scores at 6 months favoring rt-PA treatment with an odds ratio of 1.27. More deaths occurred in the rt-PA group in the first 7 days, while more deaths occurred in the placebo group after 7 days, resulting in no difference in mortality rate at the end of 6 months. Symptomatic ICH occurred more frequently in the rt-PA group (7 %) than in the placebo group (1 %), with half of these being fatal.

4 Clinical Presentation and Treatment of Acute Ischemic Stroke Stroke is broadly classified as ischemic or hemorrhagic. The acute onset of focal neurological symptoms is the characteristic presentation of stroke. The common neurological symptoms of stroke include weakness, tingling, or numbness on one side of the body, slurred speech, facial

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droop, language difficulties such as inability to follow commands or difficulty finding words, double vision, loss of vision, gait imbalance, and vertigo. Headache may be present in ischemic stroke, but is usually mild if present and not the main presenting symptom. The symptoms for ischemic stroke are usually localizable to single vascular territory. Hemorrhagic strokes present with sudden onset of severe headache with focal neurological deficits and are usually associated with nausea and vomiting. The common stroke mimics are seizures, hypoglycemia, complicated migraine, hypertensive encephalopathy, conversion disorder, and brain tumor. When evaluating a patient with suspected stroke, one of the crucial pieces of information is the time of symptom onset. If the patient is aphasic, history should be obtained from family members or friends who were with the patient when the symptoms occurred. Sometimes, the onset of stroke symptoms might not be witnessed and the patient may be found with neurological symptoms. In such cases, the time the patient was last known to be normal immediately prior to symptom discovery should be obtained. Emergency treatment includes management of the airway, breathing, circulation (ABCs) and stabilizing the patient. Patients with large ischemic strokes or hemorrhage may be obtunded and may require intubation for airway protection. Blood pressures are usually elevated. In general, blood pressures are higher with hemorrhagic stroke than with ischemic stroke. It is reasonable to lower the blood pressure to less than 185/110 during the initial evaluation of patients with suspected stroke for possible thrombolysis before the CT head results are known; intravenous labetalol, hydralazine, or nicardipine are the preferred agents [20]. If the patient with acute ischemic stroke is determined not to be a candidate for thrombolysis, then the blood pressure is not treated unless it exceeds 220/120. Intravenous fluids with 0.9 % normal saline are started because patients may be dehydrated. Oral feeds and medications are withheld until a swallowing evaluation has been performed. A blood glucose level is obtained to rule out hypoglycemia as a cause of their symptoms. Other laboratory tests to be performed include complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), INR, electrolytes, blood urea nitrogen (BUN), creatinine, and cardiac enzymes. An electrocardiogram is obtained to evaluate for atrial fibrillation or myocardial infarction. A non-contrast CT head is obtained to rule out hemorrhage. Signs of ischemic stroke are usually not seen in CT head in the first hours after stroke onset. However, subtle signs may be present, including loss of gray–white matter differentiation, obscuration of the lentiform nucleus, and sulcal effacement with less prominence of sulci and gyri. The thrombus may be visible in the large

N. Nagaraja, H. P. Adams Jr.

vessel, such as hyperdense middle cerebral artery (MCA) sign; or in a branch of MCA known as MCA ‘dot’ sign. The inclusion and exclusion criteria for the administration of intravenous rt-PA are listed in Table 2. While the use of rt-PA is not approved by the FDA in the 3- to 4.5-h time window, the AHA/ASA and the American College of Emergency Physicians in collaboration with the American Academy of Neurology recommend the use of rt-PA in the 3- to 4.5-h time window with additional exclusion criteria as listed in Table 2 [20, 21]. An informed consent is not needed to administer rt-PA. In patients not receiving oral anticoagulants and no history of thrombocytopenia or severe bleeding, rt-PA could be administered with platelet and coagulation profile results pending in the laboratory. However, treatment of patients who have taken the newer oral anticoagulants (dabigatran, rivaroxaban, and apixaban) is not recommended if the medication was taken in the previous 24–48 h. The medication is administered at a dose of 0.9 mg/kg, with a maximum dose of 90 mg; 10 % of the calculated total dose is administered as bolus over 1–2 min, and the remaining 90 % is infused over 1 h. The goal is to start rtPA within 60 min of the patient’s arrival to the emergency department. After administering rt-PA, blood pressure should be maintained at \180/105 to minimize the risk of ICH. Vital signs and neurological assessments are performed every 15 min during and after rt-PA infusion for 2 h, then every 30 min for 6 h, and then every hour until 24 h after rt-PA infusion. During and after rt-PA infusion, patients are monitored for symptoms of ICH such as severe headache, nausea, vomiting, acute increase in blood pressure, or worsening of neurological deficits. In such cases, the rt-PA is discontinued if the infusion is not completed and an emergent CT is obtained. To minimize the risk of bleeding, placement of nasogastric tubes or indwelling bladder, arterial, or venous catheters should be avoided if possible in the first 24 h after administration of rt-PA. All patients who receive rt-PA should receive follow-up imaging of the brain with CT or magnetic resonance imaging (MRI) at 24 h after rt-PA administration. Antiplatelets or anticoagulants should be administered only after 24-h brain imaging. Patients who are rapidly improving but not completely back to normal and still have disabling neurological deficits should be considered for rt-PA if no other contraindications exist because they could have long-term disabling deficits [22]. An NIHSS of zero does not necessarily indicate that the patient does not have stroke or may not have serious neurological sequelae [23]. For example, isolated hand weakness on the dominant side, which is not evaluated in the NIHSS, could be a disabling symptom that qualifies the patient for rt-PA. In some patients, it might be difficult to differentiate between a stroke mimic such as conversion

Alteplase in Acute Ischemic Stroke Table 2 Inclusion and exclusion criteria for treatment of acute ischemic stroke with intravenous recombinant tissue plasminogen activator [20] Inclusion criteria Diagnosis of acute ischemic stroke with measurable disabling neurological deficit Age C18 years Onset of symptoms or last known normal time (if symptom onset unknown) within 3 h of starting rt-PA Exclusion criteria Previous history of intracranial hemorrhage Symptoms suggestive of subarachnoid hemorrhage despite negative CT head for bleed History of stroke or significant head trauma in the past 3 months CT head hypodensity in more than one-third of the cerebral hemisphere History of aneurysm, arteriovenous malformation, or intracranial neoplasm except meningioma Recent intracranial or intraspinal surgery Untreatable high blood pressure—SBP [185 mmHg or DBP [110 mmHg Active internal bleeding Arterial puncture in noncompressible site in the past 7 days Thrombocytopenia with platelet count \100,000/mm3 INR [1.7 or PT [15 s Abnormally elevated aPTT greater than upper limit of normal Blood glucose \50 mg/dl Patients on direct thrombin inhibitors or factor Xa inhibitors with elevated sensitive test such as PTT, INR, factor Xa, thrombin time Relative contraindications Minor or rapidly improving symptoms Pregnancy Seizure at onset of symptoms Major surgery or serious trauma within 14 days Gastrointestinal or urinary tract hemorrhage within 21 days Myocardial infarction within 3 months Patients with one or more relative contraindications are considered for rt-PA with careful consideration of the risks and the benefits Additional contraindication for treatment with rt-PA in the 3- to 4.5-h time window Age [80 years NIH stroke scale [25 History of diabetes mellitus and previous stroke Use of oral anticoagulant regardless of INR aPTT activated partial thromboplastin time, CT computed tomography, DBP diastolic blood pressure, INR international normalized ratio, NIH National Institutes of Health, PT prothrombin time, PTT partial thromboplastin time, rt-PA recombinant tissue plasminogen activator, SBP systolic blood pressure

disorder from acute ischemic stroke. When in doubt, it is reasonable to treat such patients with rt-PA for suspected acute ischemic stroke because missing a stroke that could

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be treated could result in long-term disability. Studies have shown that there is no increase in risk of hemorrhage among patients with stroke mimics treated with rt-PA [24– 26]. Posterior circulation stroke symptoms such as dizziness, gait imbalance, nausea, or vomiting are commonly misdiagnosed to be secondary to peripheral ear or gastrointestinal illness. The opportunity for acute intervention with rt-PA is missed in these patients if acute ischemic stroke is not suspected in these patients. This has been encountered more commonly in young patients who are generally thought to be at less risk of stroke than older adults [27]. When in doubt, obtaining an MRI and evaluation from neurology is helpful in these patients.

5 Stroke Systems of Care Over the past 2 decades, stroke care has evolved from providing supportive care only to managing the most complex patients in comprehensive stroke centers with access to specialized personnel, diagnostic techniques, and surgical and interventional therapies. This has been possible with the implementation of several stroke care programs by the US government and professional organizations [28, 29]. Healthy People 2010, initiated by the Centers for Disease Control and Prevention (CDC), was developed to identify significant preventable health threats, increase quality and years of healthy life, and eliminate health disparities. Of the 467 objectives identified, 16 were targeted towards stroke and heart disease. The Paul Coverdell National Acute Stroke Registry, also supported by the CDC, measures and tracks acute stroke care outcomes with the long-term goal of providing the highest quality of stroke care, leading to (1) reduction in mortality, (2) reduction in severity of disability, and (3) prevention of recurrent strokes. The Stroke Center Network established an NIHSS certification program, and its data contributed to the creation of the Diagnosis Related Group Code 559 in 2005, which provided higher hospital reimbursement for patients treated with thrombolysis [29, 30]. The Stroke Center Network and the ASA also developed guidelines for stroke center infrastructure that was later incorporated by the brain attack coalition (BAC), which provided the recommendations for the establishment of Primary Stroke Center (PSC) [31]. The major elements of a PSC are (1) patient care areas—acute care teams, written care protocols, emergency medical services (EMS), emergency department, stroke unit, neurosurgical services; and (2) support services—stroke center director, neuroimaging and laboratory services, continuing medical education, and outcome- and quality-improvement activities [31]. BAC is a group of professional and governmental entities dedicated to the prevention of stroke and reducing disability and mortality from stroke.

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N. Nagaraja, H. P. Adams Jr.

In December 2003, The Joint Commission in collaboration with the AHA/ASA launched the certification process for PSC through a disease-specific certification program. The three major elements of the certification process are as follows: (1) Ensuring compliance with the use of evidence-based guidelines; (2) Implementation of Joint Commission standards; (3) Measurement of clinical outcomes with stroke performance measures. The Get With The Guidelines-Stroke (GWTG-S) is a hospital-based performance improvement program by the AHA aiming to improve adherence to evidence-based care for hospitalized stroke patients. Certification of PSCs and the GWTG-S initiative has revolutionized the quality of stroke care in the USA. It has resulted in increased thrombolysis rates and reduced mortality and length of stay rates [14]. In July 2012, the Joint Commission collaborated with the AHA/ ASA and offered the Comprehensive Stroke Centers certification to recognize the hospitals that have resources to treat complex stroke cases. These centers provide care that is not available in community hospitals or PSCs. Telestroke is a means of evaluating a patient using a high-quality bidirectional audio and videoconferencing system for the purpose of providing acute stroke care, particularly with the decision for thrombolysis. In 2009, the AHA/ASA published a review of the evidence and provided recommendations for implementations of telemedicine within the stroke systems of care [32, 33]. Only 50 % of the US population have access to a PSC within 60 min [34] and therefore telestroke has become a valuable tool to quickly evaluate patients with suspected acute stroke at non-PSCs by stroke physicians at PSCs though a hub and spoke model.

6 Future Reperfusion Therapies a.

Expanding the rt-PA Time Window With the use of advanced imaging such as CT angiogram and perfusion or MRI with perfusion to evaluate patients with acute ischemic stroke, features such as volume of core infarct, ischemic penumbra and mismatch, presence of vascular occlusion, and degree of collateral circulation are being used to select patients for intravenous or endovascular intervention at times beyond the current standard treatment window. EPITHET randomized patients to rt-PA or placebo 3–6 h after symptom onset based on diffusion–perfusion mismatch criteria. Patients who had more than 20 % mismatch had increased reperfusion with thrombolysis but this was not significantly associated with lower infarct volume [35]. There was a significant decrease in infarct volume with reanalysis of the data by co-registration techniques to identify the presence of mismatch [36].

In the DEFUSE (diffusion and perfusion imaging evaluation for understanding stroke evolution) study, patients with a perfusion–diffusion mismatch had a favorable clinical response with rt-PA when administered 3–6 h from symptom onset [37]. In this study, favorable clinical response was defined as NIHSS of 0–1 or C8 points improvement at 30 days [37]. Further analysis of the combined EPITHET and DEFUSE dataset confirmed decrease in infarct volume and increase in reperfusion in patients with mismatch [38]. EXTEND (extending the time for thrombolysis in emergency neurological deficits) is an ongoing clinical trial evaluating the efficacy of rt-PA in patients selected with significant diffusion–perfusion mismatch profile at 3–9 h from symptom onset or wake up stroke. On-going clinical trials are evaluating the safety of intravenous rt-PA, in wake up strokes or those found down with unknown last known normal time, but have early acute stroke based on imaging criteria such as diffusion-weighted imaging fluid attenuated inversion recovery (DWI-FLAIR) mismatch on MRI [39, 40]. The results of these studies could potentially extend the thrombolysis time window in select patients and also benefit those with wake up strokes. b. Adjunctive Therapies rt-PA has inherent thrombogenic properties that could result in reformation of clot after thrombolysis. A phase II study evaluating administration of rt-PA with the glycoprotein IIb/IIIa inhibitor eptifibatide within 3 h of symptom onset was found to be safe without increase in risk of symptomatic intracranial hemorrhage [41]. Combining ultrasound by transcranial Doppler during the infusion of rt-PA has showed improved recanalization rates without a significant difference in outcome [42]. c. Newer Thrombolytics In a pilot study, tenecteplase was superior to rt-PA, with higher reperfusion and clinical outcomes when it was administered 3–6 h from symptom onset in patients selected based on CT perfusion imaging [43]. Analysis of multiple studies that used desmoteplase for thrombolysis up to 9 h from symptom onset found that proximal vessel occlusion or severe stenosis was associated with favorable clinical response, defined as mRS of 0–2 or improvement in NIHSS by C8 points at 90 days [44]. A large phase III trial is ongoing to evaluate the efficacy of desmoteplase in acute ischemic stroke when administered 3–9 h from symptom onset. d. Endovascular Therapies With or Without Intravenous rt-PA The DEFUSE-2 study showed the benefit of endovascular therapy in patients with significant diffusion–perfusion mismatch compared with those without such mismatch [45]. However, the MRRESCUE (Mechanical Retrieval and Recanalization

Alteplase in Acute Ischemic Stroke

of Stroke Clots Using Embolectomy) study, which compared endovascular therapy and standard medical care, could not replicate the favorable results even in patients with a favorable mismatch profile [46]. Combining intravenous rt-PA with endovascular therapy was also not found to be beneficial compared with intravenous rt-PA alone [47]. The different mismatch criteria used in the DEFUSE-2 and MR-RESCUE studies, and the old-generation mechanical retriever devices used in the above studies, possibly accounted for their failure. Newer stent retriever devices have improved recanalization rates, and clinical trials utilizing these newer devices are ongoing to evaluate their efficacy to standard medical therapy. EXTEND-IA is comparing intravenous rt-PA alone versus intravenous rt-PA with endovascular therapy with clot retrieval in patients with major vascular occlusion and mismatch and presenting within 4.5 h of symptom onset. REVASCAT (Randomized Trial of Revascularization with Solitaire Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within 8 Hours of Symptom Onset) is another clinical trial evaluating mechanical embolectomy with the Solitaire device versus best medical therapy in anterior circulation stroke within 8 h of symptom onset.

7 Conclusion Intravenous rt-PA remains the only standard therapy available for treating patients with acute ischemic stroke presenting within 4.5 h of symptom onset. In 2013, the American College of Emergency Physicians, in collaboration with the American Academy of Neurology, published the clinical policy for the use of intravenous rt-PA for management of acute ischemic stroke in the emergency department [21]. On a national average, only 3.1 % of stroke patients receive rt-PA, with a large number of patients excluded due to delay in seeking medical attention [48]. Emergency department physicians play a crucial role in the recognition of stroke in the emergency department and activating the ‘code stroke’ process for efficient and quick evaluation of the patient for eligibility for intravenous rt-PA. Therefore, without the cordial support of the emergency department physicians, it is not possible to deliver acute stroke care to a larger number of eligible stroke patients. Intravenous rt-PA is associated with an overall 6.4 % risk of symptomatic intracranial hemorrhage and death in 3 % in the first 36 h after administration. Unfortunately, these risks are used as arguments against the administration of rt-PA, and the benefit of rt-PA in improving outcomes is forgotten. Treatment of stroke is a multidisciplinary

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approach involving the EMS, emergency department physicians, neurologists, nurses, radiology, and laboratory technicians. Every person involved in this multidisciplinary team is crucial to evaluate the stroke patient in a timely fashion and administer rt-PA for eligible patients. Hopefully, the American College of Emergency Physicians clinical policy for treatment of acute ischemic stroke with rt-PA leads to changes in emergency physician practice for acute management of stroke and results in an increase in the number of patients receiving rt-PA. Acknowledgments/Conflicts of interest Harold P. Adams Jr. MD—Dr. Adams has grant support from NINDS and St Jude Medical. He reviews outcome events for clinical trials sponsored by Merck and serves on the Data and Safety Monitoring Board for a clinical study funded by Medtronic. He is a consultant to Pierre Fabre (France). Nandakumar Nagaraja, MD, MS—Dr. Nagaraja has no disclosures. No funding was received for the preparation of this review.

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