Reperfusion Therapy for Ischemic Stroke: An Update
Reperfusion Therapy for Ischemic Stroke: An Update
Author: Jonathan Glauser, MD, FACEP, Faculty, Emergency Medicine Residency Program, MetroHealth Medical Center; Vice Chair, Department of Emergency Medicine, Cleveland Clinic Foundation, Cleveland, OH.
Peer Reviewers: J. Stephen Huff, MD, Associate Professor of Emergency Medicine and Neurology, University of Virginia, Charlottesville; and David W. Wright, MD, Co-Director, Emergency Medicine Research Center, Assistant Professor, Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA.
Stroke remains the third leading cause of death, but more importantly the cause of severe morbidity particularly among the elderly. Up to two-thirds of strokes leave the patient with significant disabilities, often requiring institutional care. This paper is an update on stroke and primarily discusses changes in stroke care over the last 5 years. The topic of thrombolytic use in stroke has not been universally accepted and in some institutions is very difficult to coordinate. Every emergency physician should understand the latest studies on thrombolytics, especially with the spread of designated stroke centers. In addition, emergency physicians should be aware of interventional radiology options for selected patients. By understanding the literature, we can help our patients make informed decisions about their best option for stroke symptoms.
—The Editor
Introduction
Ischemic stroke is a major medical problem in the United States, where approximately 600,000 new cases occur each year. In the United States and Canada, stroke is the third leading cause of death, with an age and sex adjusted incidence of approximately 1000 per 100,000 in the 65-74 year group and approximately 2000 per 100,000 in the 75-84 year group.1 The regional impairment of blood flow in a specific cerebrovascular distribution causes stroke symptoms. If blood flow is restored within a critical time frame, there is functional recovery of the ischemic penumbra. The hypothesis that intravenous thrombolytic therapy may restore blood flow and improves outcomes in acute ischemic stroke was not tested in large randomized trials until the 1990s.
Stroke trials generally measure the extent of neurologic deficit by the National Institute of Health Stroke Scale. (See Table 1.) Outcomes typically are measured by NIH score improvement or worsening,2 or by Modified Rankin Scale (See Table 2) or Barthel Index.3,4 Major stroke studies use these scales to assess severity of deficit and to track improvement or worsening with treatment.
| Table 2. Modified Rankin Scale (mRS)3 |
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The National Institute of Neurologic Disorders and Stroke Study (NINDS)
The first successful large prospective trial of therapy for acute ischemic stroke was announced in December 1995.5 This trial changed the attitude that there was little benefit to active therapy of the leading cause of neurologic disability in America except for supportive care and rehabilitation. The NINDS rt-PA study group reported that patients given recombinant tissue plasminogen activator (rt-PA) intravenously within three hours of onset of ischemic stroke were at least 30% more likely to have minimal or no disability three months later (relative improvement—absolute improvement was 12%), compared with patients who received placebo. In this study, "minimal or no disability" corresponded to a Barthel Index of 95-100 or Modified Rankin Scale of 0-1. (See Table 2.) A total of 624 patients with symptoms of acute ischemic stroke were assigned randomly to treatment with rt-PA (alteplase) or placebo within three hours of symptom onset. The dose of rt-PA given was 0.9 mg/kg up to 90 mg; 10% as a bolus, the rest to be infused over 60 minutes. The incidence of symptomatic brain hemorrhage within the first 36 hours was 6.4% in the rt-PA group, versus 0.6% in the placebo group (p< .001), but there was no significant difference in overall mortality between the two groups. Treatment with alteplase led to a complete recovery at three months as measured by the NIH stroke scale in 38% of patients, compared with 21 per cent who received placebo.5 The Food and Drug Administration subsequently approved IV rt-PA for acute ischemic stroke in June 1996. The first guidelines for the use of thrombolytic treatment published by the American Heart Association appeared in 1997.6 The NINDS alteplase stroke study is the only large randomized trial that documented benefit from the treatment of acute ischemic stroke with intravenous thrombolytic therapy. The success of the trial is felt to be related to its strict exclusion criteria and its treatment of patients within 3 hours of symptom onset. (See Table 4.)
| Table 4. Trials Using Thrombolytic Agents* |
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The impact of the NINDS study has been felt in many ways. The NINDS trial specified that treatment be started within 180 minutes of onset of symptoms. Some regions of the country have made tremendous efforts to educate patients, families, and medical emergency personnel to call for rescue help earlier for possible neurologic events. Hospitals have organized to offer emergency treatment for stroke, including urgent imaging, and to obtain specialty stroke center certification. Efficient use of CT scanning and public education are essential elements required to increase the number of patients eligible for thrombolytic therapy.
Historical Perspective: Other Intravenous Thrombolytic Trials
A number of trials have examined the use of thrombolytic agents with time windows beyond three hours in the treatment of acute ischemic stroke. These trials demonstrated that thrombolytic agents were not indicated beyond the three-hour window.
One of the early trials of rt-PA demonstrated that the incidence of symptomatic intracranial hemorrhage was significantly higher for patients treated between 6 and 8 hours after symptoms began than in those treated within 6 hours.7
The Multicenter Acute Stroke Trial- Italy (MAST-I) and the Australian Streptokinase Trial (AST) both suggested that most excess hemorrhages and early deaths occurred in patients treated after three hours. The MAST-I study, published in 1995, randomized 622 patients with acute ischemic stroke to one of four treatment arms: a) 1.5 million units of intravenous streptokinase (SK) over one hour, b) 300 mg aspirin/day for 10 days c) Both streptokinase and aspirin in the above doses; or d) placebo. The window of treatment for the study was six hours from symptom onset. Enrollment was terminated after an interim analysis showed a statistically significant increase in the six-month mortality among the patients treated with SK and aspirin.8 This treatment arm had a lower rate of disability. However, the combined end point of death or disability did not differ significantly among the four treatment groups.
The Multicenter Acute Stroke TrialEurope (MAST-E) published in 1996 randomized 310 patients from France and the United Kingdom with acute ischemic stroke to treatment within six hours of symptom onset with either placebo or SK 1.5 million units over one hour. The study was terminated after an interim analysis showed a significantly higher mortality rate among SK-treated patients that was significant at 10 days and approached significance at three months (45% vs 34%, p = 0.06). There was no significant difference between groups in the primary composite of death and disability at 6 months.9
The Australian Streptokinase (ASK) Trial published in 1996 randomized 340 patients from 40 participating centers in Australia with acute ischemic stroke to treatment within six hours of symptom onset with either placebo or SK 1.5 million units over one hour. The study was terminated early when an interim analysis revealed a significantly higher 90-day mortality among SK-treated patients (43% vs 22%).10 A post-hoc analysis suggested that treatment of patients more than three hours after the onset of symptoms increased the risk of adverse outcomes.11
The European Cooperative Acute Stroke Study group (ECASS-I) treated 615 study patients, and evaluated rt-PA 1.1 mg/kg body weight given intravenously within six hours of onset of symptoms and reported no benefit in the treated group. The upper dose limit was 100 mg per patient, with a bolus of 10% of the dose given over 1-2 minutes, followed by a 60-minute infusion. The occurrence of large parenchymal hemorrhages was significantly more frequent in the rt-PA treated patients than in the placebo group. Mortality rates were higher in the rt-PA treated groups (17.9%) than in the placebo group (12.7%). However, there was a significant improvement in clinical outcomes at 3 months in a population derived by excluding 109 "protocol violators"—patients with extensive pre-treatment CT abnormalities. The authors concluded in their report, published in 1995, that "intravenous thrombolysis cannot be currently recommended for use in an unselected population of patients with acute ischemic stroke."12 The task of finding an appropriate target population for thrombolysis depended on the accurate recognition of early CT findings of infarction.
A retrospective analysis of the ECASS-I trial analyzed only the 87 patients in the cohort treated within three hours of symptom onset. The primary endpoints included combined Barthel Index and Rankin Scale, long-term Scandinavian Stroke Scale, National Institutes of Health (NIH) Stroke Scale, mortality at 30 days and at 90 days, and occurrence of intracranial hemorrhage. The mortality was somewhat higher in the rt-PA treated group (21%) vs. placebo (15%), and intracranial hemorrhage occurred significantly more often in the rt-PA treated group than in the placebo group. However, all other outcome measures indicated a benefit to rt-PA administration. The percentage of patients in the most severely disabled group (modified Rankin Scale 4 or 5) was 35% in the placebo group and 11% in the rt-PA group. It is notable that the dose of rt-PA was approximately 20% higher than in the NINDS group. The authors of this analysis concluded that the ECASS-I data supported the efficacy of early thrombolytic therapy in acute hemispheric stroke patients in the 0-3 hour cohort.13 It is notable, however, that the occurrence of early CT signs is not necessarily time-dependent, but rather may be linked to the site of underlying arterial occlusion and the quality of the residual collateral blood supply.14
Controversies and Problems with Acceptance of Thrombolysis: Community Reports
Thrombolytic drugs have the potential to cause morbidity and mortality, and have not always been used successfully. Several published community studies provide some insights into the difficulties that administration of rt-PA may present.
A retrospective cohort of community-based patients given thrombolysis for acute stroke from May 1, 1996 through December 31, 1998 was conducted on 63 patients treated for acute stroke in 16 community hospitals in Connecticut. This was a fairly exhaustive effort to identify every patient in the state who was treated with thrombolytic therapy for acute stroke during that period. Some hospitals had policies in place that they did not give rt-PA for stroke. Of the 63 patients, 42 (67%) had at least one major protocol deviation, and 61 (97%) had major or minor protocol deviations. Overall in-hospital mortality was 25%, compared with 30-day mortality in the NINDS cohort of 13%. Serious extracranial hemorrhage was 13% in the Connecticut cohort vs. 2% in the NINDS group. Minor protocol deviations included admission blood glucose levels below 50 mg/dL or greater than 400 mg/dL.
The rate of intracranial hemorrhage in the Connecticut cohort was 17% compared with 11% in the NINDS cohort. The major protocol variations included any contraindication in the rt-PA insert: rtPA dosing errors (weight was not recorded in 35%), initiation of therapy more than three hours after symptom onset, bleeding diathesis (elevated PT or PTT, low platelet count), or evidence for active internal bleeding. Three patients had a history of recent trauma; all of these had an adverse event, including death or hemorrhage. In 21% of cases, stroke diagnosis was not made by a neurologist using the NIHSS. In 6 out of 63 cases, there was edema, shift, or evidence for herniation on the initial CT. However, when cases without major protocol deviations were eliminated, mortality in the Connecticut cases was 14%—roughly the same as the NINDS cohort.15 This suggests that appropriate use of screening, laboratory testing, medication dosing, and post-treatment care might replicate the NINDS results.
Other reports suggested that the clinical application of thrombolytic therapy in the community might not replicate the results of clinical trials in academic centers. A study of Indianapolis, Indiana hospitals treating 50 patients with rt-PA from July, 1996 to February 1998 suggested a rate of symptomatic intracranial hemorrhage approximately twice as high (12%) as that reported by NINDS. Protocol violations were found in 8 cases, in which 6 hemorrhagic complications occurred.16
A larger cohort study of 3948 patients with ischemic stroke admitted to 29 hospitals in the Cleveland area over the one-year period July 1997 to June 1998 reported on the use of rt-PA in the community setting. Of these, 70 (1.8%) received intravenous rt-PA, of whom 15 (22%) had an intracranial hemorrhage (ICH), 11 (15.7%) had a symptomatic ICH, 6 (8%) of which were fatal. The total rate of ICH was 22%. In-hospital mortality was significantly higher among patients treated with rt-PA (15.7%) compared with patients not receiving rt-PA (5.1%, p < 0.001). The higher in-hospital mortality likely was due to the occurrence of ICH, since 55% of the deaths in patients receiving rtPA occurred in patients with symptomatic ICH. Fifty percent of those treated had deviations from national treatment guidelines. For example, the use of antiplatelet agents or anticoagulants occurred in 37.1% of patients, and 12.9% of patients were treated beyond the 3-hour time window. Of the 17% of ischemic stroke patients arriving within 3 hours of symptom onset, 10.4% received IV rt-PA.17 This was an attempt to analyze stroke care in community hospitals outside the NINDS trial.
Those investigators found that their quality improvement initiative implemented as a result reduced protocol violations from 50% to 19% in participating hospitals, and a subsequent study from that same region showed a lessened complication rate, with overall 2.7% of patients with ischemic stroke treated within the 3 hour time window. By tightening control over protocol violations with quality improvement initiatives, including 24-hour stroke beepers, stroke and emergency medicine committees, and decreasing protocol violations, the incidence of intracranial hemorrhage declined to 6.4% in the nine Cleveland-area hospitals participating. The major deviations from protocol which made the difference included: treating only patients whose symptoms were fewer than three hours in duration, elimination of deviations from blood pressure management, and avoidance of thrombolysis in patients previously anti-coagulated.18,19
A report from the United Kingdom described the results of thrombolytic therapy and reported data from three centers that utilized rt-PA after 2001. Of 120 patients who received thrombolysis for acute ischemic stroke, 5% developed symptomatic cerebral hemorrhage, and 31% of recipients achieved a good outcome at three months as measured by a Modified Rankin Scale of 0-1.20
The Canadian Alteplase for Stroke Effectiveness Study (CASES) was a national prospective cohort study, conducted to assess the effectiveness of alteplase therapy for ischemic stroke in actual practice in Canada. Cases were compiled from 1999 through June 30, 2001, with 90-day follow-up. A registry was established to collect data over 2.5 years as a condition for licensure of rt-PA mandated by the federal government in that country. A total of 1135 patients were enrolled at 60 centers in Canada, and data were available for 1110 patients. Symptomatic intracranial hemorrhage occurred in 4.6% of patients. Outcome events were collected and rated using the modified Rankin Scale, with excellent functional outcome being an mRS of 0 or 1. A return to pre-stroke functioning was seen in 36.8% of patients.21
A nationwide analysis was derived from the Nationwide Inpatient Sample (NIS), the largest all-payer discharge database in the United States, over the period 1999-2002. There were 2594 patients treated with thrombolysis out of a group of 248,964 patients admitted with the diagnosis of acute ischemic stroke. The rate of intracerebral hemorrhage in the thrombolysis cohort was 4.4%, and 0.4% for non-thrombolysis patients. The mortality rate in-hospital was 11.4% for the thrombolysis group, vs. 6.8% for the non-thrombolysis cohort. The rate of discharge home was 37.5% for the thrombolysis cohort and 46.4% for the non-thrombolysis cohort.22 This was a descriptive report only, and the authors concluded that thrombolysis as it is used in the community has a safety profile similar to that observed in prospective clinical trials. One reason for this conclusion was that, even when intracerebral hemorrhage was excluded as a cause, the mortality rate in the thrombolysis group remained higher than that of the non-thrombolysis group (10.2% vs 6.7%, p < 0.001), emphasizing that the higher mortality in this group was a function of baseline differences in the patients rather than treatment-related.
Therefore thrombolytics can be given in the community setting; however, there must be strict adherence to NINDS protocols.
Criticisms and Misgivings Regarding Acceptance of Thrombolytic Therapy
There have been criticisms of the NINDS study itself. Critics note that it was performed by researchers with an interest and presumed expertise in the treatment of acute stroke. The trial design used a means of accelerating early recruitment by not permitting centers to randomize patients in the 91-180 minute time period if they had recruited three more patients in that time stratum compared to the 0-90 minute period. The benefits seen in the NINDS trial, therefore, may be due to half of the patients being treated within 90 minutes of stroke onset. There also was some baseline imbalance in stroke severity of patients in the rt-PA and placebo-treated groups, resulting in an over-representation of milder strokes in the alteplase group. Translation of clinical trial data and guidelines into general clinical practice entails: physician awareness and familiarity with data and guidelines, physician agreement with data, the personal expectation of benefit to the patient, the belief that one can deliver the therapy effectively, and overcoming other barriers affecting physician behavior, including inertia.23,24,25 Some or all of these factors may be in play in the emergency physician community.
Physician aversion to the rate of iatrogenic hemorrhagic complications may override the concern over adverse outcomes associated with the natural course of the disease. A recent survey of 1105 emergency physicians who were active members of the American College of Emergency Physicians indicated that 24% were "unlikely" or "very unlikely" to use rt-PA for stroke, with another 16% uncertain, even in the ideal setting with the ideal candidate. Most (65%) were concerned about the possibility of hemorrhage, while 23% cited lack of benefit as reasons for not using the drug, and 12% cited both reasons. Emergency physicians were most likely to use rt-PA if there was an institutional commitment to deliver thrombolytic therapy to acute stroke patients, including active support from neuroradiology and neurology.26
There are other barriers to the prompt management of acute ischemic stroke. Patients or family members may not recognize symptoms of stroke or seek urgent help, and time remains the most frequent exclusionary factor. There may be a failure of general practitioners or paramedics to recognize the urgency of treatment. Consent for thrombolysis may be difficult and, as noted above, physicians may have uncertainties about administering thrombolysis. Neuroimaging may be delayed.27 Even among specialists, there may be uncertainty as to the use of thrombolysis. One study in 1998 indicated that only 16% of neurologists had ever administered the treatment.28
Exclusion Criteria for Thrombolysis
Exclusion criteria for thrombolysis in the management of acute stroke have varied slightly by study. The NINDS data are summarized in Table 4. In both the ATLANTIS (described below) and NINDS trials, patients were excluded if they had suffered a stroke or serious head trauma within the preceding three months, had major surgery within 14 days, had gastrointestinal or genitourinary bleeding within 21 days, or had arterial puncture at a non-compressible site within seven days. Any history of intracranial hemorrhage or symptoms suggestive of subarachnoid hemorrhage were exclusionary. Blood pressure levels above 185 mm systolic or 110 mm diastolic—or patients requiring aggressive therapy to lower blood pressure to these levels—were also exclusionary criteria.
Coagulation criteria for exclusion included oral anticoagulation, heparin administration within 48 hours, platelet counts under 100,000, a prothrombin time greater than 15 seconds, and an elevated PTT. (See Table 3.)
| Table 3. Inclusion and Exclusion Criteria in the NINDS Trial* |
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The ATLANTIS trials had slightly different exclusionary criteria: stroke within 6 weeks and major surgery within 30 days. For the ECASS investigators, major surgery or arterial puncture within 3 months, and hematocrit less than 25 were exclusionary.29 Seizures and resolving symptoms generally are exclusionary factors as well, though not specifically listed in these trials.
More difficult is the determination of exclusionary criteria from the CT scan. Few emergency physicians are proficient enough at CT interpretation to feel confident in their interpretation. When possible, CT interpretation should be performed by a radiologist or neurologist. Early infarct signs such as diffuse swelling and parenchymal hypodensity, with or without effacement of cerebral sulci in more than 33% of the middle cerebral artery territory, were exclusionary for ATLANTIS B and for ECASS. The hyperdense middle cerebral artery sign (HMCAS) is a marker of thrombus in the middle cerebral artery, and is associated with severe brain ischemia and poor outcome. The specificity of the HMCAS for middle cerebral artery occlusion approaches 100%.30 The HMCAS did not serve as an exclusion criterion for the ECASS study. Early extensive CT changes and severity of the initial neurologic deficit are the best predictors of risk of hemorrhage.31
Emergency physicians may find a tutorial on CT interpretation available at http://www.strokecenter.org/education/ais_ct_tool/ to be particularly helpful.
Early signs of infarction on CT and an NIHSS score of greater than 20 often are considered reasons to avoid thrombolysis, as post hoc analysis of NINDS data indicates that this group derived little if any benefit from thrombolysis. The duration of occlusion and degree of collateral blood flow, as determined by SPECT scanning, was associated with hemorrhagic transformation in one small study.32 Specific exclusionary factors are continuing to evolve as the attempt to optimize risk/benefit with thrombolytic therapy evolves.
Controlling the Incidence of Intracerebral Hemorrhage
Certain other factors play a role in increasing risk of hemorrhagic transformation (HT) of a stroke. Caution has been advised in the use of thrombolysis in patients older than 80 years. Baseline systolic blood pressure as well as extent of parenchymal hypoattenuation or mass effect on baseline CT were risk factors for intracranial hemorrhage on secondary analysis of ECASS II data.33 Data analysis indicates that low platelet count and increased blood sugar concentrations are risk factors for symptomatic intracerebral hemorrhage as well.21,34
A comprehensive review of factors associated with in-hospital mortality after administration of thrombolysis using accumulated Nationwide Inpatient Sample (NIS) data from 995 hospitals recently has been published. Advanced age, increased time from stroke onset to treatment, congestive heart failure, and atrial fibrillation/flutter were independent predictors of in-hospital mortality after thrombolysis.22
Treatment with Thrombolytic Agents: Reports Since NINDS, ECASS-I, and MAST
NINDS, ATLANTIS, and ECASS II gave a total of 0.9 mg/kg body weight of rt-PA up to a maximum of 90 mg. ECASS I used a total dose of 1.1 mg/kg of rt-PA up to 100 mg maximum. All of these studies gave 10% of the dose as a bolus during the first minute, with the remainder infused over 1 hour.
The Alteplase Thrombolysis for Acute Noninterventional therapy in Ischemic Stroke (ATLANTIS) study enrolled 613 acute stroke patients from 140 community and teaching hospitals in North America and was published in 1999. Patients were randomized to receive either 0.9 mg/kg of rt-PA or placebo, administered from 0 to 6 hours after symptom onset. Because of safety concerns, in December 1993 the time window was changed to 0-5 hours after symptom onset. Enrollment was based on CT and clinical criteria. Despite a significant increase in the rate of symptomatic intracranial hemorrhage, rt-PA patients treated within 3 hours of symptom onset were more likely to have a very favorable outcome (NIHSS score of 0 or 1) at 90 days compared to placebo.35
Most of the patients enrolled in the study were treated more than 3 hours after stroke onset. Of the 547 patients who received study medication between three and five hours after stroke onset, the results from the rt-PA treated group were not favorable. In this group, mortality at 90 days was 6.9% with placebo and 11% with rt-PA. Symptomatic intracerebral hemorrhage within 10 days of treatment was 7.0% in the rt-PA group and 1.1% in the placebo group. Fatal intracerebral hemorrhage occurred in 0.3% of the placebo group and 3.0% of the rt-PA group (p < 0.001). For the primary end point in the target population, 32% of placebo patients and 34% of rt-PA patients had an excellent recovery at 90 days (p = .65). The authors concluded that the results did not support the use of rt-PA for stroke treatment beyond three hours. There was an equal lack of efficacy in patients treated between three and four hours of stroke onset and patients treated between four and five hours. Treatment with rt-PA produced a significant increase in the rate of both symptomatic and asymptomatic intracerebral hemorrhage.36 This study highlighted the need for treatment within three hours of symptom onset if intravenous thrombolysis is to be employed.
The ECASS II study was an attempt to duplicate the ECASS I study without the protocol violation of including patients with early infarct signs of more than one-third of the middle cerebral artery territory. This trial enrolled 800 patients in Europe, Australia, and New Zealand. The same dose of rt-PA of 0.9 mg/kg up to 90 mg total was administered as in NINDS, and patients were enrolled within 6 hours of stroke onset. In this trial, 80% of patients were enrolled between three and six hours of symptom onset. Using a 90-day modified Rankin score of 0-1 as the primary end point, 40% of the rt-PA group and 37% of the placebo group had a good outcome (p = .28). Symptomatic ICH was noted in 8.8% of the rt-PA treated patients and in 3.4% of placebo-treated patients (p < .05). While the ECASS II study failed to find a significant treatment benefit for any of the planned secondary end points, in a post hoc analysis 54% of the rt-PA- treated patients and 46% of the placebo-treated patients were independent at day 90 (p = 0.02).37
The STARS (Standard Treatment with Alteplase to Reverse Stroke) study was mandated by the FDA. This was a prospective cohort study of 389 acute ischemic stroke patients who were given rt-PA. This study was conducted primarily in centers with stroke expertise. The median time from stroke onset to alteplase administration was 2 hours 44 minutes. The results demonstrated a 13% 30-day mortality rate and 3% symptomatic intracerebral hemorrhage rate.38
The Desmoteplase in Acute Ischemic Stroke Trial (DIAS) published in 2005 was an MRI-based acute stroke thrombolysis trial utilizing intravenous desmoteplase. Desmoteplase, the plasminogen activator recombinant Desmodud Salivary Plasminogen Activator a-1 rDSPA, is a highly fibrin-specific and non-neurotoxic thrombolytic agent. Desmoteplase shows a 72% structural homology to rt-PA, and is derived from the saliva of a South American vampire bat. Because it is more fibrin-selective and more specific than rt-PA, desmoteplase has the theoretical advantage of lower risk of bleeding and shorter time to lysis. DIAS was a placebo-controlled randomized double-blind trial. Patients with NIHSS stroke scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. The agent was administered 3-9 hours after symptom onset. Reperfusion rates using desmoteplase 125 mg/kg were 71.4% compared with 19.2% with placebo (p = 0.0012). Favorable 90-day clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index was found in 22.2% of placebo-treated patients and in 60% of desmoteplase-treated patients (p = 0.009). Favorable 90-day outcomes occurred in 52.5% of patients experiencing reperfusion, vs. 24.6% of patients without reperfusion. Initially higher doses of desmoteplase were utilized, but it was noted that fixed doses of 25 mg, 37.5 mg, or 50 mg of desmoteplase caused excessive rates of symptomatic intracranial hemorrhage. A notable aspect of this study was the use of magnetic imaging to attempt to identify the ischemic penumbra (potentially salvageable tissue), as well as the use of a thrombolytic agent up to 9 hours from stroke onset. The lesion on diffusion-weighted imaging (DWI) presumably reflected irreversibly damaged brain tissue, while an area of perfusion deficit on perfusion MRI (pMRI) may be a marker of salvageable brain tissue. DWI may delineate infarcted brain tissue in less than one hour after symptom onset, possibly within minutes.39 Eligible patients had to show at least a 20% perfusion/diffusion mismatch involving hemispheric gray matter. DIAS was the first prospective placebo-controlled randomized acute stroke thrombolysis trial to use MRI both for patient selection and as a primary efficacy endpoint. A longer stroke onset to treatment interval was not associated with a reduction of treatment effect, suggesting that beyond three hours from onset of stroke the presence of perfusion/diffusion mismatch as a marker of tissue at risk may be a more important predictor of response than duration of symptoms. Most notably, using MRI criteria for enrollment, the rate of symptomatic intracranial hemorrhage was not higher in the group treated later than five hours from stroke onset than those treated before five hours.40
The DIAS trial called into question the optimal imaging which should be obtained to guide thrombolytic therapy. Clear demarcation of the irreversibly damaged core and the ischemic but still viable and salvageable tissue at risk is seen on diffusion-weighted imaging/perfusion-weighted imaging (DWI/PWI) MRI, as above. The other critical part of the diagnostic workup consists of the accurate assessment of vascular and morphological status, demonstrating presence and site of vessel occlusion. CT angiography (CTA) can reliably detect intracranial stenosis, emboli, and aneurysms of moderate and larger size. CTA may give information about collateral circulation and increase the sensitivity for early ischemic changes not seen on non-contrast CT scans. Therefore, CTA source images (CTA-SI) may give information similar to that of the DWI/PWI mismatch concept used in the DIAS study. It has been suggested that CTA-SI or stroke MRI for DWI/PWI be employed to delineate ischemic but still viable and salvageable tissue before thrombolysis is initiated within 3-6 hours of stroke onset—with or without Doppler ultrasound to demonstrate recanalization.41 Imaging may give an more accurate evaluation of the time of stroke onset than may be obtained by historical data. A disadvantage to reliance on use of magnetic resonance/DWI is that stroke mimics have been shown to be associated with abnormal DWI: active multiple sclerosis plaques, status epilepticus, herpes encephalitis, and highly cellular intracranial tumors. Acute hemorrhage can be more difficult to identify on MRI than on CT.42 Another major disadvantage to reliance on MR scanning is that there is a large fraction of patients who have contraindications to MR scanning because of medical instability, hypoxia, restlessness, or medical hardware such as pacemakers. MRI also is less widely available than CT.
Recent Data and Meta-Analyses
Different thrombolytic agents have been utilized in various studies, coupled with the fact that studies vary with doses used and differing time limits for administration of thrombolytic agents. As well, severity of illness and differing enrollment criteria vary by report. For all of these reasons, a variety of meta-analyses have been published to make sense of the risks and benefits of thrombolytic therapy for acute ischemic stroke. The reason for the large number of meta-analyses is evident. Unlike the mega-trials of thrombolysis for acute myocardial infarction, which had enrollments in the tens of thousands of patients, by 2003 there were fewer than 6000 patients in the Cochrane Library systematic review of thrombolysis for acute ischemic stroke.43
An important meta-analysis combined data from six trials: two from the NINDS, two from the ECASS, and two from ATLANTIS. This meta-analysis was performed on a total of 2775 patients randomized to receive placebo or rt-PA within 360 minutes of stroke onset. The median onset to start of treatment (OTT) was 243 minutes. Odds of a favorable three-month outcome increased as OTT decreased. Odds were 2.81 (95% confidence interval CI 1.8-4.5) for an OTT of 0-90 minutes, 1.55 (CI 1.1-2.2) for 91-180 minutes, 1.4 (CI 1.1-1.9) for 181-270 minutes, and 1.2 (CI 0.9-1.5) for 270-360 minutes in favor of the rt-PA group. Hemorrhage was seen in 5.9% of rt-PA patients and 1.1% of controls (p < 0.00001). The hazard ratio for death was not statistically different between the treated and placebo groups except at intervals of 271-360 minutes, where the hazard ratio was 1.45 (1.02-2.07 CI). In this analysis, 59.8% of those with parenchymal hematoma died within three months: 62.2% for rt-PA, and 46.7% for placebo.29
An earlier meta-analysis was performed of the NINDS, ECASS I and ECASS II data. This suggested a benefit to therapy even within 6 hours of stroke onset, and indicated that the odds ratio of intracerebral hemorrhage was only slightly higher in the 6-hour time window (3.23) than it was in the 0-3 hour time window (2.68). Even incorporating the results of the ATLANTIS study, in which the 3-5 hour time window failed to show any benefit to thrombolytic therapy, the authors found a benefit to treating patients within a 3-6 hour time window, with a number needed to treat of 25 to derive benefit. Defining disability and death as an mRS score greater than 3, rt-PA treatment led to a significant 37% reduction within six hours compared to placebo.44
In the Cochrane Library, all randomized placebo-controlled trials of any thrombolytic agent in patients with ischemic stroke were included. As of 2000, there were 5216 patients in 17 trials, 2889 of these from rt-PA trials. Thrombolytic therapy significantly increased the risk of death within the first 10 days (odds ratio 1.85, CI 1.48 to 2.32). The main cause for the increase in deaths was fatal intracerebral hemorrhage after thrombolysis (odds ratio 4.15). Despite this, thrombolytic therapy administered up to 6 hours after stroke onset significantly reduced the proportion of patients who were dead or dependent (mRS > 3), (OR 0.83). The number needed to treat to prevent 1 death or disability was 7 in the 3 hour time window after onset of stroke.45
Most recently, data from the Cochrane Library indicates the following: treatment with alteplase (rt-PA) is associated with an excess of deaths, approximating 19 extra deaths per 1000 patients treated. Thrombolysis, regardless of which drug is used, increases the rate of fatal intracranial hemorrhage approximately four-fold (odds ratio 4.34, p < 0.00001). Despite these risks, thrombolysis with rt-PA reduces the risk of death and disability, with the benefit being equivalent to approximately 55 extra independent survivors per 1000 treated. There was a trend toward better outcome for those patients treated within 3 hours of stroke onset, associated with approximately 100 more independent survivors per 1000 treated. Patients with NIHSS scores of 6-20 benefitted the most. Those whose score was less than 5 tended to do well with or without treatment. Those with scores greater than 22 had higher risk of hemorrhage.46
It is notable that the point estimate of a favorable outcome is close to 1.0 at 360 minutes (1.2, 95% confidence interval 0.9-1.5), suggesting reduced probability of benefit to thrombolysis beyond this time. Presumably, the ischemic penumbra is not salvageable by then. These results were consistent with findings from a previous trial in which investigators utilized transcranial doppler to correlate time to arterial recanalization with neurological recovery at 24 hours after administration of rt-PA. No individual had early complete recovery if an occlusion persisted for more than 300 minutes. Partial or complete recanalization of the occluded artery took place within 60 minutes of the start of treatment in 75% of those in whom recanalization occurred. These data support a therapeutic window of from 240-270 minutes from the onset of stroke symptoms.47
Thrombolytic Therapy in the Community Setting: The Current Standard
Intravenous tissue plasminogen activator (rt-PA) is the only FDA-approved treatment for reperfusion in acute ischemic stroke. (Other treatments are available in terms of supportive care.) It must be administered within three hours of symptom onset. The frequency of symptomatic hemorrhage, cited as 6.4% in the NINDS study, has been matched in the community setting. Inclusion criteria include patients aged 18 years and older with clinical diagnosis of ischemic stroke causing a measurable neurological deficit.
Exclusion criteria by CT scan will evolve as more is learned, as discussed earlier, but include evidence for intracranial hemorrhage on non-contrast head CT, or a high clinical suspicion for subarachnoid hemorrhage even with a normal CT. A full list of exclusionary criteria has been listed. (See Table 4.) The most frequent violations of protocol that have been associated with hemorrhage have been:
- Administration of thrombolysis to patients with blood pressure elevations above prescribed limits of 185 systolic or 110 diastolic which require more than simple measures such as nitropaste or intravenous labetolol to attain these levels by the time of initiation of thrombolysis;
- Administration of thrombolysis to patients with bleeding diathesis: platelet count less than 100,000/mm3, prothrombin time greater than 15 seconds, or recent anticoagulant use; and
- Treatment beyond three hours of symptom onset.
CT exclusionary criteria may be more accurately detected with interpreters specifically trained in neuroradiology or by transmission of images vie tele-radiography. Once a decision is made to administer rt-PA, the dose is 0.9 mg/kg, up to a maximum of 90 mg, with 10% of the dose given as a bolus followed by an infusion lasting 60 minutes. Central venous access and arterial puncture should be restricted for 24 hours after thrombolytic therapy. Thrombolytic therapy should be used only in facilities prepared to deal with bleeding complications. Neurological worsening mandates discontinuing the rt-PA infusion, and obtaining a CT as an emergency. Bleeding may mandate administration of cryoprecipitate, fresh frozen plasma, platelets, or packed red blood cells.
It has been shown that patients arriving by ambulance receive more prompt therapy. Time guidelines may be difficult to follow, but certain NINDS time targets are worthy of mention regarding stroke treatment: time to physician evaluation within 10 minutes, time to CT within 25 minutes of arrival, and time to CT interpretation within 45 minutes of patient arrival.5,48
Intra-Arterial Thrombolysis
Thrombolytic agents have been used intra-arterially (IA) in acute ischemic stroke since the 1980s.49,50 Localized IA thrombolysis has the theoretical advantage of achieving faster, more complete recanalization using less fibrinolytic drug than IV therapy.
IA therapy entails a complete four-vessel cerebral angiogram from a transfemoral approach. This technique allows evaluation of the site of vessel occlusion, extent of thrombus, number of territories involved, and collateral circulation. Good leptomeningeal collaterals may limit the extent of ischemic damage and prolong the therapeutic window. An MRA or CT angiogram (CTA) can first be done to identify the primary site of occlusion. Superselective angiography through a microcatheter is performed at regular intervals to assess for degree of clot lysis and to adjust the volume of thrombolytic agent. The goal is to achieve rapid recanalization with as little thrombolytic agent as possible to limit brain infarction and to reduce the risk of hemorrhage. Local fibrinolysis makes it possible to monitor the frequency of recanalization as well as how fast it occurs. IA thrombolysis affords less systemic thrombolytic activity. Even with direct IA application, all current single thrombolytic agents often require 30-60 minutes for recanalization. Intravenous heparin generally is administered during IA thrombolysis to reduce the risk of catheter-related thromboembolism and to prevent early re-occlusion.
Clot composition plays a key role in the rapidity and degree of recanalization achieved. Fresh thrombi are rich in fibrin and plasminogen and are easier to lyse than aged atherothrombi, which are more organized, have low fibrin and plasminogen contents and high amounts of platelets and cholesterol. Commercially available agents include urokinase (UK), recombinant tissue-plasminogen activator (rt-PA), reteplase (r-PA), and tenecteplase (TNKase). UK is not fibrin-selective and may cause systemic hypofibrinogenemia. Rt-PA and r-pro-UK are fibrin-selective and are only active at the site of thrombosis.
The efficacy of clot lysis is related to the site of occlusion, as well as the volume, age, and composition of the clot. Recanalization rates are lower with occlusions in large vessels vs. smaller ones, and with intravenous regimens vs. intra-arterial ones. For example, the recanalization rate for internal carotid occlusions is less than 20% within eight hours. For proximal middle cerebral artery occlusions, the reperfusion rate exceeds 60% with intra-arterial regimens. Intra-arterial thrombolysis for basilar artery occlusions may have a recanalization rate of nearly 80%, but the artery often re-thromboses. For lacunar infarcts, the diameter of the occluded artery may be 100-200 mm—smaller than the resolution of angiography.51 Limitations of IA therapy, apart from its inability to intervene in small vessel occlusions include that it is time-consuming and may be impractical to perform urgently in many settings.
Two notable trials have been performed in IA thrombolysis. The Prolyse in Acute Cerebral Thromboembolism trials (PROACT I and PROACT II) were reported in 1998 and 1999 respectively.52,53 Each utilized pro-urokinase (r-pro-UK) as the lytic agent in patients with angiographically proven middle cerebral artery (MCA) occlusion. Pro-urokinase is a recombinant single chain zymogen of an endogenous fibrinolytic agent, UK. Neither trial allowed mechanical disruption of clot.
In the PROACT I and II trials, heparin was used at a dose of 2000 units bolus followed by 500 units/hr for 4 hours.54
The PROACT I trial randomized 40 patients at a median 5.5 hours from symptom onset, with 26 receiving r-pro-UK and 14 receiving placebo. The study compared 6 mg IA r-pro-UK with saline placebo in patients with ischemic stroke of less than six hours duration. NIHSS scores for inclusion ranged from 4 to a maximum of 30. The recanalization rate was 57.7% in the r-pro-UK group and 14.3% in the placebo group. Initially, a higher dose of heparin was used: 100 units/kg bolus and 1000 units/hr for 4 hours, but the rate of symptomatic hemorrhage was 27%, prompting the reduction in heparin dosing to 2000 units bolus and 500 units/hr as above. With reduced heparin dosing, the ICH rate decreased to 6%. There appeared to be a 10-12% increase in excellent outcomes in the IA r-pro-UK group at 90 days as compared to placebo.52
The PROACT II trial utilized a 9 mg dose of r-pro-UK and the low-dose heparin as in the later phase of PROACT I. The median time from symptom onset to initiation of IA thrombolysis was 5.3 hours. Only patients with anterior circulation/middle cerebral artery ischemia were enrolled. The primary outcome of PROACT II was the proportion of patients with a modified Rankin score of 2 or less at 90 days, signifying slight or no neurologic disability. Recanalization rates at 2 hours were 66% for the treatment group and 18% for the placebo group (p < 0.001). Excellent neurological outcome and the ability to live independently were attained by 40% of patients treated with r-pro-UK and 25% in the heparin-only group (p = 0.04). Symptomatic brain hemorrhage occurred in 10% of the r-pro-UK group and in 2% of the control group. There was no excess mortality in the treated group (24%) vs. the control group (27%).53
IA thrombolysis requires access to a team of physicians capable of performing the procedure. In PROACT II, the median time to drug infusion after stroke onset was 5.3 hours. Based on that study, a 6-hour window may be a realistic goal for treatment of ischemia in the MCA distribution. Pro-urokinase has not been FDA approved for this use.
IA thrombolysis may have a special role in vertebrobasilar occlusion. Mortality rates for acute basilar artery occlusion have been cited as 83-91%.55,56 There often is a need for angioplasty of an underlying basilar artery stenosis. Mortality was 90% in patients not responding to recanalization compared with 31% in patients achieving at least partial reperfusion.55 Of those with successful recanalization, most have only mild or moderate disability, compared with fewer than 14% of patients whose vessels remain occluded.57 Neurointerventional therapy with thrombolysis is the only lifesaving therapy that has shown some benefit in this patient population, although no randomized trials have been published.58
A meta-analysis of 27 studies involving 852 patients receiving IA thrombolysis showed favorable outcomes significantly greater in the IA group vs. control (41.5% vs 23%, p = 0.002), with lower mortality (27.2% vs 40%). Symptomatic intracerebral hemorrhage occurred in 9.5% of the IA group.59 The larger studies involving IV and IA thrombolysis are listed in Table 4.
A disadvantage of IA thrombolysis is delay to treatment. The median time to treatment in the PROACT studies was approximately 5.5 hours, entailing a gathering of a neurointerventional team and transport to an angiography suite. Every 10-minute delay in time to treatment produces a measurable reduction in the probability of a good outcome.25 For this reason, interest has developed in combining IV and IA therapy.
The pilot Emergency Management of Stroke (EMS) Bridging Trial combined IA and IV thrombolysis. The intent was to take advantage of the early infusion possible with IV administration with the greater recanalization efficacy—and titrated dosing allowing limited thrombolytic dosing—of IA therapy. Patients with stroke less than 3 hours duration were given a smaller (0.6 mg/kg) loading dose of IV rt-PA followed by angiography. Of all patients, 70% still had residual clot. If a clot was visualized, treatment with IA rt-PA was initiated with 20 mg of the drug over 2 hours or until recanalization had been achieved. There was an improved middle cerebral artery reperfusion rate in patients who received IA rt-PA (55% vs 10% achieving full recanalization), but there was also an increased risk of life-threatening bleeding complications. There was no difference in seven-day or three-month outcomes.60
The Interventional Management of Stroke (IMS) was a follow-up trial using combined IV/IA therapy, enrolling patients with ischemic stroke from 17 centers with a baseline NIHSS score of greater than 10. Primary comparisons were with similar subsets of placebo and rt-PA treated patients from the NINDS stroke trial. The IV dose, to be given within three hours of stroke onset, was 0.6 mg/kg followed by angiography. If an arterial occlusion was present, up to 22 mg rt-PA was infused over two hours. The median time to IV therapy was 140 minutes, and to IA therapy was 212 minutes. The symptomatic brain hemorrhage rate was 6.2% in patients receiving both IV and IA rt-PA, and 90-day outcomes compared favorably (28% of IMS patients) with those from the NINDS trial placebo (15%).61
Intra-arterial delivery of thrombolytic agents seem to lyse clots more effectively than IV rt-PA and has extended the time window to intervention up to six hours. It takes longer than IV thrombolysis and no head-to head studies of IA vs. IV therapy have been performed. Complications of femoral access unique to IA thrombolysis include pseudoaneurysms and retroperitoneal hemorrhage.59
A combined therapy of intra-arterial rt-PA and IV abciximab platelet inhibition has been employed with some favorable results in acute vertebrobasilar occlusion. This regimen afforded a lower median total rt-PA dose of 20 mg, and allowed percutaneous transluminal stenting in cases of persistent vertebrobasilar occlusion. Of 47 patients enrolled in the combined local Fibrinolysis and intravenous Abciximab in acute vertebrobasilar Stroke Treatment (FAST) study, mortality was only 38%, with 34% favorable outcome utilizing combined therapy. This compares favorably with a mortality rate based upon historical controls approaching 90% for vertebrobasilar occlusion.62
Ultrasound may enhance thrombolysis by cavitation of the thrombus, resulting in increased surface area. Phase I data of the Combined Lysis Of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic TPA (CLOTBUST) have been published. A total of 55 patients were treated. Nonrandomized patients receiving 0.9 mg/kg of rt-PA within three hours of stroke onset were monitored with portable transcranial doppler (TCD) equipment and a standard head frame to fix the probe position. Overall intracranial hemorrhage rate was 5.5%. Complete recanalization was found on TCD in 20 of 36 patients, with overall improvement in NIHSS of over 4 points at 24 hours in 49%. Enhancement of thrombus dissolution was achieved with 2 MHz frequency ultrasound. The relatively narrow ultrasound beam can be focused at the presumed intracranial thrombus location as monitored by TCD. The authors concluded that continuous TCD insonation for up to two hours is safe and may be therapeutically effective.63 Extracranial and transcranial Doppler ultrasound also has been utilized to monitor recanalization after thrombolytic therapy. TCD measuring flow velocities in the middle cerebral artery and its major branches performed with a hand-held probe was shown to correlate with recanalization and clinically significant recovery in one series of 41 unselected patients with ischemic stroke.64
Mechanical Interventions
New techniques for mechanical clot removal have been in feasibility and safety trials in the United States and Europe. Techniques include direct mechanical balloon angioplasty of the thrombus, mechanical snaring of clot from the middle cerebral artery, and use of suction thrombectomy devices for reperfusion.65,66 Current limitations of these techniques include the relatively large catheter size and limited flexibility in accessing tortuous intracranial vessels. Dramatic neurologic improvement has been reported in patients treated with intravenous thrombolytics within 3 hours of symptom onset subsequently shown to have an occlusion of a proximal cerebral vessel on CT angiography.67 Since transcranial Doppler data indicate that time to complete restoration of blood flow after the beginning of rt-PA infusion, if it is to occur, is 42 minutes on average, it appears that the optimal time to imaging after rt-PA may be 45-60 minutes after infusion onset.68
One successful mechanical strategy utilizes the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) device. The MERCI retriever is a tapered wire with five helical loops of decreasing diameter from 2.8 to 1.1 mm at its distal end. The clot in the occluded vessel is snared and aspirated out through the guide catheter. A phase I trial for evaluation of safety and efficacy for this device has been completed, enrolling 30 patients at 7 centers in the United States. Successful recanalization was achieved in 43% of patients and with rescue thrombolysis in addition, the recanalization rate was 64%. There were no symptomatic intracranial bleeds. Of 18 patients successfully revascularized, 9 made significant recovery, whereas 0/10 patients who were not revascularized successfully made a significant recovery. The median time from completion of baseline CT to groin puncture was 2 hours 23 minutes, and time to completion of treatment was approximately another 1 hour 20 minutes.69
In 2005, the safety and efficacy of the device was published in the MERCI trial. The Merci retriever achieved recanalization in 48% (68/141) of patients in whom the device was employed. Intra-arterial thrombolytics were allowed in cases of treatment failure with this device. Symptomatic intracranial hemorrhages occurred in 7.8% of patients, and good neurological outcomes were more frequent at 90 days in patients with successful recanalization compared with patients with unsuccessful recanalization (46% vs 10%, p < 0.0001). Mortality was lower as well in the group successfully recanalized (32% vs 54%, p = 0.01).70 Complications of use of the MERCI retrieval system include vascular perforation, embolization of a previously uninvolved territory, and intramural arterial dissection.
In 2004, the FDA approved the MERCI retriever for removal of blood clot in patients experiencing ischemic stroke who are otherwise ineligible for IV rt-PA, or in whom IV rt-PA treatment has failed. It is the only mechanical device for treatment of acute stroke that has been approved by the FDA, although a randomized trial has not been performed to address its safety and efficacy. It possibly has extended the time window for treatment of stroke beyond the six-hour time limit of IA thrombolysis to eight hours. That figure was arrived at from PROACT II, where the maximal time from onset to starting thrombolysis was six hours—with an additional infusion time for pro-urokinase of two hours.58
Confounding Factors
It has been demonstrated that patients with more severe strokes arrived earlier in the emergency department than did those whose condition was less severe. Thus, studies have shown high mortality and disability in early treatment intervals. These patients represent those who have the most to gain from treatment, as rt-PA has greatest effect in those treated early. Therefore, time-to treatment data must be adjusted for differences in baseline stroke severity.
It has been suggested based upon a small pilot study. that there may be a high rate of intracranial hemorrhage or death after rt-PA administration in blacks. A retrospective chart review of 19 patients treated at Harlem Hospital in New York City over a five-year period showed that 8 patients suffered intracranial hemorrhage, and 6 died. National guidelines for treatment with rt-PA were followed. All were hypertensive blacks.71 The role of ethnic background in response to thrombolysis remains to be defined.
The Emergency Department and Stroke Centers
Recommendations for the establishment of primary stroke centers were published in 2000 and are in use today.72 Major elements of a primary stroke center are summarized in Table 5. It is recommended that the acute stroke team include at a minimum one physician and another health care professional who are available 24 hours every day. A member of the team should be at the patient’s bedside within 15 minutes of being called. A log should be kept that documents call times, response times, patient diagnoses, treatments, and outcomes. The availability of protocols for use of rt-PA in acute stroke is a key step in reducing rt-PA-related complications.
| Table 5. Major Elements of a Primary Stroke Center |
|
|
An EMS call for a possible stroke should be assigned a high priority to ensure rapid evaluation and transport. The issue of whether EMS personnel should transport patients with acute stroke only to facilities with a stroke center has not been resolved. It is likely that ED personnel will be members of a hospital’s stroke team.
The Brain Attack Coalition, which published these guidelines, also recommended that neurosurgical care for the patient be available within two hours of when it is deemed clinically necessary. This means that the patient could be transferred to another facility with a neurosurgeon on call—or the neurosurgeon could be on call at the initial hospital.
A primary stroke center should have a designated medical director who has training and expertise in cerebrovascular disease. Qualifications for such a director might include: completion of a stroke fellowship; participation as an attendee or faculty in at least two regional, national, or international stroke courses or conferences each year; five or more peer-reviewed publications on stroke; eight or more continuing medical education credits each year in the area of cerebrovascular disease; or other criteria agreed on by local physicians and hospital administrators.
Primary stroke centers should have the capability to perform a CT scan within 25 minutes of the order being written, and to have the scan interpreted by experienced physicians within 20 minutes of its completion. These persons could be available by remote access (teleradiology). Laboratory results should be completed within 45 minutes of being ordered. Door-to-needle treatment for the use of rt-PA should be no more than 60 minutes.
It also was recommended that pre-specified committees meet and review/modify practice patterns at least three times per year. Estimated annuals costs for operating a primary stroke center have been between $8000 and $200,000.72
Further Challenges and Future Studies
Goals for thrombolytic therapy in the future have been enumerated: treatment of 15-20% of patients with acute stroke, achievement of a reperfusion rate greater tahn 70%, reduction of hemorrhagic complications to less than 3%, and obtaining functional recovery in greater than 60% of patients.34 In the future, serum markers may be able to predict those at risk of developing intracerebral hemorrhage after thrombolysis. Matrix metalloproteinases (MMP) are up-regulated after ischemia and disrupt the blood-brain barrier favoring edema and hemorrhage. A correlation also has been noted between the plasma concentrations of one of the components of the basilar lamina, the cellular fibronectin, and parenchymal hemorrhage in patients treated with rt-PA.73 Plasma MMP-9 greater than 140 ng/mL and cellular fibronectin greater than 4.4 mg/mL predict hemorrhagic infarction with high sensitivity and specificity.34
The role of platelet glycoprotein IIb/IIIa receptor inhibitory agents has been investigated in small non-controlled studies with a combination of IV rt-PA and infusion of tirofiban. Recanalization occurred in 68% of patients.74,75 A recent trial comparing abciximab alone to placebo, the AbESTT trial, suggested a non-significant shift toward good functional outcome in patients treated within five hours from onset of stroke. The loading dose of abciximab was 0.25 mg/kg bolus followed by 0.125 mg/kg/min infusion for 12 hours. Symptomatic intracerebral hemorrhage occurred in 3.6% of patients treated with abciximab vs. 1% with placebo. Though not powered for efficacy, functional outcomes at 3 months indicated that significantly more abciximab patients had mRS scores of 0 or 1 than placebo (53.9% vs 34.6%).76 A larger phase III trial utilizing abciximab has been initiated, with a smaller group to receive the drug later than 4.5 hours after stroke onset or 2.5 hours after awakening with stroke symptoms.77
It has been noted that acute stroke care entails more than thrombolysis. Early mobilization and management of hydration, fever, and hypoglycemia have all been cited as essential supportive care.78,79 Anti-platelet therapy may entail aspirin, which in patients with prior transient ischemic attack (TIA) or stroke has been shown to reduce recurrent non-fatal stroke by 23%.80 The Chinese Acute Stroke Trial (CAST) randomized 21,106 patients with acute stroke to receive 160 mg/day of aspirin or placebo for 28 days. Compared with placebo, aspirin reduced mortality (3.3% vs 3.9%) and the rate of non-fatal stroke or death (5.3% vs 5.9%).81 The International Stroke Trial (IST) involved 19,435 patients randomized to receive aspirin, low-dose heparin, and high-dose heparin for 14 days. Compared with patients who did not receive aspirin, those who received aspirin had lower rates of recurrent ischemic stroke (2.8% vs 3.9%) and of non-fatal stroke or death (11.3% vs 12.4%).82
Additional trials are under way to further delineate a time beyond which thrombolytic therapy might be of benefit. IST3 (6000 patients) utilizes rt-PA 90 mg/kg up to 90 mg, with a 0-6 hour time window, using clinical and CT scan criteria. ECASS III (800 patients) employs the same dose of rt-PA, with a 3-4 hour time window. DIAS (630 patients) will employ escalating doses of desmetoplase, from 25 to 37.5 to 50 mg, with a 3-9 hour time window based on advanced MR scanning criteria. EchoPlanar Imaging THrombolysis Evaluation Trial (EPITHET- 100 patients) uses advanced MR scanning criteria (PWI/DWI mismatch > 1.2).46
These randomized and blinded trials should shed some light on the role of stroke MRI and CTA in evaluating the safety of thrombolysis beyond the 3 hour time window. SYNTHESIS is an ongoing study of IV (up to 3 hours) vs. IA (up to 6 hours) rt-PA. FRALYSE is an ongoing study comparing 2 doses of rt-PA (0.8 mg/kg versus 0.9 mg/kg over 90 minutes) with a time window of 6-7 hours.83
MR RESCUE is an ongoing trial with a therapeutic window of 8 hours aimed at determining responders to the MERCI retriever in patients stratified by MRI mismatch as described earlier. The current IMS trial, when completed, will furnish data on the relative efficacy of combined IV/IA therapy compared to IV alone. IMS II is a study with planned enrollment of 120 patients identical to IMS except that the catheter that delivers the thrombolytic drug also delivers low-intensity ultrasound within the thrombus to accelerate clot lysis.58
Conclusions
There are findings to suggest that the beneficial effect of rt-PA might extend beyond three hours in a subset of patients, although the approved use of rt-PA has been restricted to within 3 hours of stroke onset. It is possible that the time window for thrombolysis for certain subtypes of stroke could extend up to and beyond six hours. Recanalization rates approximating 64-66% may be feasible with current pharmacology and technology. The major factor that accounts for declining benefit of thrombolysis with time may be the progressive disappearance of the ischemic penumbra. Selecting reperfusion therapy in the future will not be based solely on time of onset, a neurologic score, and a routine CT scan. Improved patient selection will be critical in the successful management of the stroke patient. The use of MRI and CT angiography for selecting acute stroke patients for thrombolysis after three hours of onset, and the potential usefulness of new biomarkers of blood brain barrier disruption, and hemorrhagic risk are yet to be defined.
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Stroke remains the third leading cause of death, but more importantly the cause of severe morbidity particularly among the elderly. Up to two-thirds of strokes leave the patient with significant disabilities, often requiring institutional care.Subscribe Now for Access
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