Marc Fisher, MD

 Current therapy for acute ischemic stroke remains limited to intravenous recombinant tissue plasminogen activator (tPA) administered within 3 hours of symptom onset, but despite strong evidence supporting its effectiveness,1-5 only 2% to 4% of all stroke patients currently receive tPA.4   The major impediment to use of tPA is the late arrival of many stroke patients at the emergency department for evaluation and treatment. Fortunately, other treatment options are on the horizon.   THE 3- TO 6-HOUR WINDOW   The value of intravenous tPA given outside the 3-hour window is being studied. Although the efficacy of thrombolysis initiated later than 3 hours after the onset of acute ischemic stroke has not been proved in a clinical trial, 2 metaanalyses suggest that intravenous tPA significantly reduces the risk of disability and death when started between 3 and 6 hours later. The number needed to treat (NNT) was 11 (0 to 6 hours) or 25 (3 to 6 hours); for intravenous tPA initiated within 3 hours, the NNT was 8.6,7 Additional trials in the 3- to 6-hour window are needed to establish efficacy and to determine tablish efficacy and to determine which patient subgroups are most responsive. For now, however, thrombolytic therapy with tPA in the 3- to 6-hour window should not be initiated outside of research protocols.   Although administration of tPA more than 3 hours after symptom onset may benefit some patients, the interval between onset of symptoms and initiation of thrombolysis remains an essential factor in treatment, because therapeutic efficacy decreases even within the 3-hour window.2 To achieve optimal results, thrombolysis should be initiated as soon as possible after the onset of stroke.8 Thus, the ability to achieve rapid stroke onset- to-hospital and door-to-needle times will continue to be an important factor in the management of acute stroke.   Appropriate patient selection is crucial--especially to prevent bleeding. How to determine which patients are the best candidates for tPA treatment is a matter of ongoing investigation. In a recent report from a single center, among 216 patients treated with tPA, predictors of lack of response to treatment were glucose levels greater than 144 mg/dL, cortical involvement determined by clinical features, and time to treatment.9 In addition, other factors that appear to affect the risk/benefit ratio of thrombolysis for a particular patient include:    

Extent of signs of early infarct on CT scan. 

Initial severity of stroke, based on National Institutes of Health Stroke Scale (NIHSS) score. 

The patient's age.    Whether patients with extensive early ischemic changes on the initial CT scan are eligible for tPA during the first 3 hours after symptom onset remains an unanswered question. The only CT cri- terion currently required for intravenous tPAtreatment (based on results of the National Institute of Neurological Disorders and Stroke [NINDS] trial) is the exclusion of intracerebral hemorrhage (ICH). A reevaluation of NINDS CT data showed no correlation between early infarct signs and either outcome or ICH rate.10   However, other studies have reported that an early CT hypodensity covering more than half of the middle cerebral artery (MCA) territory is associated with an 85% risk of fatal outcome and that patients with a hypodense area of more than one third of the MCA territory receive no benefit from tPA treatment and are at increased risk for symptomatic ICH.11,12 These large hypodensities represent irreversibly damaged tissue. Among stroke experts, there is a growing consensus that patients with signs of profound ischemia and a large hypodensity on a CT scan should not be treated with tPA--even within the 3-hour window-- because of the excessive risk of ICH and the likelihood that they will not respond to therapy.   Some experts advise against the use of intravenous tPA in patients with very mild (NIHSS score less than 4) or severe (NIHSS score greater than 25) stroke. In the former setting, the natural history is favorable, and in the latter, the risk of ICH and poor outcome is high.13,14 However, precise clinical criteria for these exclusions have not been established. The prognosis for patients with basilar artery occlusion is poor, with a high degree of associated mortality. In some centers, intra-arterial thrombolytic therapy is used and improved outcome has been observed. In a recent study, the efficacy of intravenous tPA for basilar occlusion was reported. Patients were treated up to 12 hours after onset when onset of symptoms was sudden and up to 48 hours after onset when symptoms were determined to be gradually progressing.15 Partial or complete reperfusion was observed in 26 (60%) of 43 patients with followup vascular imaging. At 3 months, 20 of 50 had died, and 12 patients (24%) were performing activities of daily living independently.   As for elevated blood glucose levels, the effects of admission hyperglycemia on stroke outcome are still not fully understood, and there are still no data that show the impact that maintenance of euglycemia during an acute stroke has on outcomes. However, several clinical studies have shown an association between admission hyperglycemia and poor outcome.16,17   In a retrospective analysis of 1205 patients with acute ischemic stroke who received intravenous tPA, a normal pretreatment blood glucose level was an independent predictor of a good outcome.18 An analysis of the NINDS trial data showed that higher glucose levels on admission were associated with a significantly reduced likelihood of a desirable outcome and a significantly increased risk of symptomatic ICH--regardless of tPA treatment.19 It remains to be determined whether these findings represent a cause-and-effect relationship or a stress response reflective of more severe stroke. Lowering an elevated blood glucose level during acute stroke to as close to a normal value as possible may be an optimal strategy. However, at this time, no clear evidence exists to justify withholding tPA treatment because of hyperglycemia in patients who have acute ischemic stroke.   Imaging of cerebral ischemia has progressed in recent years and holds promise as a tool that can improve patient selection. In patients with acute stroke, diagnostic imaging must be able to:  

Accurately assess vascular status (the presence and location of vessel occlusion).   

Accurately assess tissue injury (demonstrate both irreversibly damaged brain tissue and potentially salvageable ischemic tissue).  

Reliably exclude ICH.   New MRI sequences and modern CT techniques, such as CT angiography and perfusion CT, may have the potential to fulfill these criteria. Diffusion-weighted MRI (DWI) can delineate ischemic brain tissue within minutes of stroke onset, while perfusionweighted MRI (PWI) defines the area of cerebral hypoperfusion. The absolute volume difference-- or ratio of PWI to DWI ("mismatch")-- reveals ischemic tissue that may be at risk for irreversible damage but is still potentially salvageable (the "ischemic penumbra"). MR angiography can reliably assess vessel status, and T2 sequences can establish a diagnosis of ICH within the first hours after stroke onset.20   Together, these MRI findings make it unnecessary to rely on a therapeutic window that is defined strictly by time and permit individualization of the time window for each patient, although controversy over specific MRI criteria for thrombolysis remains. A recent nonrandomized trial that involved 139 patients showed that "stroke MRI"-guided tPA therapy appears to be safe and effective beyond a 3-hour window.21 This observation will have to be proved in a randomized placebo-controlled clinical trial.   There have been concerns that MRI might be insensitive for the detection of ICH and could not be used alone for early stroke diagnostic imaging. A recent study comparing MRI with CT for detection of acute ICH demonstrated that gradient-recalled echo MRI was more sensitive than CT for hemorrhage detection.22   INTRA-ARTERIAL THROMBOLYSIS   Intra-arterial thrombolysis may offer the advantages of higher recanalization rates and shorter times to eventual recanalization. 23,24 In patients who have vertebrobasilar thrombosis, intra-arterial thrombolysis is the only therapy to date that has reduced mortality and improved outcomes. Moreover, the window for thrombolysis in the posterior circulation-- while not currently established-- may be 12 hours or more after stroke onset. However, these findings are not from a randomized trial.   There are only 2 published randomized studies of intra-arterial thrombolysis, and the procedure is not FDA-approved. The Prolyse in Acute Cerebral Thromboembolism (PROACT) trials I and II showed that intra-arterial thrombolysis administered within 6 hours of stroke onset was more beneficial than an intravenous approach in patients with severe stroke (NIHSS score between 11 and 20) secondary to proximal occlusion of the MCA.23 However, the investigators employed an agent (recombinant prourokinase) that is not available for clinical use. Most centers that perform intra-arterial thrombolysis use tPA, and data on the efficacy and safety of intra-arterial administration of tPA are limited.   Two additional problems restrict the use of this therapy: 

Limited availability of centers with experienced personnel and immediate access to angiography and interventional neuroradiology.

The delay required to mobilize the resources to perform the intraarterial procedure.   A pilot study that investigated the combination of low-dose intravenous tPAgiven within 3 hours of symptom onset and intra-arterial tPA given later demonstrated the feasibility and safety of this approach. Additional study is required to prove its effectiveness.25   OTHER EXPERIMENTAL RECANALIZATION STRATEGIES   Thrombolytic agents. Reteplase, a third-generation tPA, has been used in small series of patients with acute stroke but has yet to be evaluated in a controlled trial.26 The lytic agent desmoteplase (which has a longer half-life than tPA) was tested in the Desmoteplase in Acute Stroke (DIAS) study in a 3- to 9-hour window in patients with proven MCA occlusion and a significant PWI/DWI mismatch. The study demonstrated substantially better early reperfusion with desmoteplase and also clinical efficacy with the highest dose used in this dose-escalation study.27 An additional study to confirm this preliminary finding has been completed, and more extensive studies are being planned. Evidence from a series of clinical trials suggests that another agent, ancrod, an enzyme that degrades fibrinogen, may improve outcomes in patients treated within 3 hours of the onset of stroke.28   Further, 2 studies have shown that abciximab, a glycoprotein (GP) IIb/IIIa receptor antagonist, has a reasonable safety profile and shows a trend toward benefit in treated patients.29 Combinations of tPA or reteplase and a GP IIb/IIIa receptor antagonist (abciximab30 or integrilin31) used in intra-arterial therapy in small series of patients with acute ischemic stroke appeared to be safe. In 37 patients who had severe stroke (average NIHSS score, 19), use of intravenous integrilin and intra-arterial tPA showed a trend toward better revascularization and clinical outcome compared with intra-arterial tPA alone.31   Endovascular interventional techniques include balloon angioplasty, mechanical removal of clots,32 laser-assisted thrombolysis of emboli, and use of ultrasoundassisted devices.33 All of these techniques are still in the experimental stage. Recently, however, the FDA approved a clot retriever that takes its name from the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial. The Merci Retriever removes clots within the intracranial vessels. It has been approved only for clot removal, not stroke treatment. It remains unclear how safe or effective the Merci Retriever is in the setting of acute ischemic stroke.   Multimodal approaches. Intravenous or intra-arterial administration of thrombolytic agents or GP IIb/IIIa inhibitors has been used to enhance the effect of mechanical clot lysis.29,30 Ongoing and future trials of various thrombolytic agents combined with different mechanical devices (and based on advanced imaging techniques) may provide important information about the feasibility and efficacy of multimodal therapy for acute stroke.   An interesting recent report describes the use of continuous 2- MHz transcranial Doppler ultrasound in conjunction with intravenous tPAinitiated within 3 hours of stroke onset in 126 patients.34 The primary end points of the study were complete recanalization demonstrated within 2 hours or dramatic clinical improvement. Complete recanalization occurred in 46% of patients treated with ultrasound and tPA and in only 18% of the patients treated with tPA alone. Clinical recovery within 2 hours occurred in 29% of patients in the group that received ultrasound and tPA and in 21% of patients in the tPA-alone group. This preliminary study suggests that continuous ultrasound can enhance early clot lysis and may improve clinical outcome.   NEUROPROTECTIVE THERAPY   The time required for brain tissue ischemia to progress to irreversible injury varies depending primarily on the severity of the reduction in cerebral blood flow.35 The cellular events associated with the progression of injury--collectively referred to as the ischemic cascade-- are complex and multifactorial. The existence of an ischemic penumbra, which is suggested by the DWI/PWI mismatch, implies that neuroprotective therapies that target aspects of the ischemic cascade might potentially salvage some portion of the penumbra, if therapy is initiated in a timely fashion and the drug can reach the affected tissue. The Table lists the types of agents that have been evaluated in clinical trials as neuroprotective drugs. Unfortunately, so far none has demonstrated unequivocal efficacy, and none is currently approved for use in patients with stroke. However, many new trials of neuroprotective drugs are under way.   The complexity of the ischemic cascade suggests that a drug that targets only 1 aspect of brain injury caused by ischemia will likely have only modest benefits at best.36 Targeting multiple aspects of the ischemic cascade simultaneously is another approach to neuroprotection. 37 This can be done by using combinations of drugs that each attack a different aspect of the cascade. However, a "cocktail" approach to neuroprotective therapy will be difficult because of regulatory concerns about the testing of 2 unapproved drugs simultaneously and the potential for drug-drug interactions that could affect the safety of the trial.   An alternative neuroprotective strategy that targets multiple aspects of the ischemic cascade is the use of a single drug with multiple effects. Currently available drugs such as desferrioxamine, nicotinamide, and tacrolimus have multiple mechanisms of action. An approach that used one of these drugs would avoid many of the pitfalls associated with trials of unapproved drug combinations. However, none of these drugs has been studied in patients with acute ischemic stroke; they have only been suggested for study.   Neuroprotective drugs also might be used in combination with thrombolysis. This strategy has the potential to provide maximum Categories of neuroprotective drugs evaluated in clinical trials Voltage-regulated calcium channel antagonists NMDA and AMPA antagonists Sodium channel antagonists GABA antagonists Free radical scavengers and antagonists Serotonin agonists Maxi-K channel agonists Growth factors Antiadhesion molecules Nootropic agents NMDA, N-methyl-D-aspartate; AMPA, 2-(aminomethyl)phenylacetic acid; GABA,  -aminobutyric acid. benefit. One way to do this would be to give a safe and effective neuroprotective drug before a patient's arrival at the hospital.38 The neuroprotective drug would enhance the survival of the ischemic penumbra, which would both increase the amount of ischemic tissue that is potentially salvageable and extend the time window for successful thrombolysis. Another way to combine neuroprotection and thrombolysis might be to give a neuroprotective drug after successful thrombolysis to impede the development of reperfusion injury. 39 Reperfusion injury is now well documented in experimental studies, and preliminary MRI data in humans also suggest that secondary injury does occur in some patients with stroke after blood flow to ischemic brain tissue has been reestablished. ?   Editor's Note:Aprevious version of this article was published in the January 2004 issue of Consultant. It has been updated and revised for Applied Neurology.   REFERENCES   1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587. 2. Fisher M, Brott TG. Emerging therapies for acute ischemic stroke: new therapies on trial. Stroke. 2003;34:359-361. 3. Kwiatkowski T, Libman R, Frankel M, et al, and the NINDS rt-PA Stroke Study Group. The NINDS rt-PA Stroke Study: sustained benefit at one year [abstract]. Stroke. 1998;29:288. 4. O'Connor RE, McGraw P, Edelsohn L. Thrombolytic therapy for an ischemic stroke: why the majority of patients remain ineligible for treatment. Ann Emerg Med. 1999;33:9-14. 5. Heuschmann PU, Kolominsky-Rabas PL, Roether J, et al. Predictors of in-hospital mortality with acute ischemic stroke treated with thrombolytic therapy. JAMA. 2004;292:1831-1838. 6. Hacke W, Brott T, Caplan L, et al. Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology. 1999;53(suppl 4): S3-S14. 7.Wardlaw J, del Zoppo G, Yamaguchi T. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2000;(2):CD000213. 8. Adams H, Brott T, Crowell R, et al. Guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1994;25:1901-1914. 9. Saposnik G, Young B, Silver B, et al. Lack of improvement in patients with acute stroke after treatment with thrombolytic therapy: predictors and association with outcome. JAMA. 2004;292: 1839-1844. 10. Patel SC, Levine SR, Tilley BC, et al; National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Lack of clinical significance of early ischemic changes on computed tomography in acute stroke. JAMA. 2001;286: 2830-2838. 11. Larrue V, von Kummer R, del Zoppo G, Bluhmki E. Hemorrhagic transformation in acute ischemic stroke. Potential contributing factors in the European Cooperative Acute Stroke Study. Stroke. 1997;28:957-960. 12. von Kummer R, Meyding-Lamade U, Forsting M, et al. Sensitivity and prognostic value of early CT in occlusion of the middle cerebral artery trunk. Am J Neuroradiol. 1994;15:9-15. 13. von Kummer R, Allen KL, Holle R, et al. Acute stroke: usefulness of early CT findings before thrombolytic therapy. Radiology. 1997;205: 327-333. 14. Hacke W, Kaste M, Skyhoj Olsen T, et al. European Stroke Initiative (EUSI) recommendations for stroke management. The European Stroke Initiative Writing Committee. Eur J Neurol. 2000;7: 607-623. 15. Lindsberg PJ, Soinne L, Tatlisumak T, et al. Long-term outcome after intravenous thrombolysis of basilar artery occlusion. JAMA. 2004;292: 1862-1866. 16. Weir CJ, Murray GD, Dyker AG, Lees KR. Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow up study. BMJ. 1997;314:1303-1306. 17. Bruno A, Biller J, Adams HP, et al. Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology. 1999;52: 280-284. 18. Demchuk AM, Tanne D, Hill MD, et al. Predictors of good outcome after intravenous tPA for acute ischemic stroke. Neurology. 2001;57:474-480. 19. Bruno A, Levine SR, Frankel MR, et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology. 2002;59: 669-674. 20. Schellinger PD, Fiebach JB, Hacke W. Imaging- based decision making in thrombolytic therapy for ischemic stroke: present status. Stroke. 2003;34:575-583. 21. Rother J, Schellinger PD, Gass A, et al. Effect of intravenous thrombolysis on MRI parameters and functional outcome in acute stroke 

Articles

Current therapy for acute ischemic stroke remains limited to intravenous recombinant tissue plasminogen activator (tPA) administered within 3 hours of symptom onset, but despite strong evidence supporting its effectiveness,1-5 only 2% to 4% of all stroke patients currently receive tPA.

Marc Fisher, MD

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Stroke: While Current Treatment Is Limited, New Options Are on the Horizon