Currently, the only approved therapy for acute ischemic stroke is tissue plasminogen activator (tPA), initiated within 3 hours of stroke onset. New patient selection criteria are emerging that may improve the effectiveness and safety of thrombolysis. For example, evidence of extensive early ischemia on CT may predict a poor outcome regardless of whether tPA is administered. New imaging techniques, such as diffusion MRI, perfusion MRI, and MR angiography, may be able to identify salvageable tissue and distinguish it from irreversibly damaged tissue. Such findings may allow the 3-hour window for tPA therapy to be extended in certain patients. Other approaches to ischemic stroke therapy that are being studied include intra-arterial thrombolysis, new thrombolytic agents, platelet aggregation inhibitors, endovascular interventional techniques (alone and in combination with pharmacologic thrombolysis), and neuroprotective therapy with various agents to ameliorate the consequences of ischemia in brain tissue.
Although current therapy for acute ischemic stroke remains limited to intravenous recombinant tissue plasminogen activator (tPA) administered within 3 hours of symptom onset, other treatment options are on the horizon.
Here we discuss recent and ongoing research that may:
CURRENT THERAPY: tPA AND THE 3-HOUR WINDOW
In 1996, the FDA approved the use of intravenous tPA for acute ischemic stroke. This was a landmark in the history of stroke treatment; before that time, thrombolytic therapy was not recommended for patients with stroke.
The approval of tPA was based primarily on the results of the National Institute of Neurological Disorders and Stroke (NINDS) tPA Stroke Study, in which 624 patients with ischemic stroke received placebo or tPA within 3 hours of symptom onset. Approximately 50% of study participants were treated within 90 minutes of stroke onset.1 Initiation of tPA therapy within 90 minutes was associated with an odds ratio of 2.83 for a favorable outcome (95% confidence interval [CI], 1.77 to 4.53); if therapy was started between 90 and 180 minutes after symptom onset, the odds ratio was 1.53 (95% CI, 1.11 to 2.11).2
The patients who had received tPA had a 30% greater probability of recovering with little or no deficit after 3 months, as assessed by multiple outcome measures. The benefits associated with tPA treatment were maintained at 1 year.3
Patients who were most likely to have an excellent outcome were those younger than 75 years and those who had a mild to moderate stroke (as indicated by a score of less than 20 on the National Institutes of Health Stroke Scale [NIHSS], which is available at www.strokecenter.org/trials/scales/ nihss.pdf.). Nonetheless, tPA treatment improved the likelihood of a favorable outcome in patients with severe stroke (NIHSS score greater than 20) and in older patients.1
The major risk associated with tPA treatment was symptomatic intracerebral hemorrhage (ICH), which occurred in 6.4% of patients who received tPA but in only 0.6% of those in the placebo group. However, there was no significant difference in mortality at 3 months (17% of patients who received tPA and 20% of those who received placebo) or at 1 year (24% and 28%, respectively).1,3
Since the NINDS study results were published, several other groups have reported similar efficacy and safety data for tPA treatment. Despite this strong evidence, 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. Thus, it is important to teach patients about the signs and symptoms of stroke so they know when to seek medical care.
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 meta-analyses suggest that intravenous tPA significantly reduces death and disability 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 8.5,6 Additional trials in the 3- to 6-hour window are needed to establish 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 attempted 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. Not only does the risk of ICH increase with time, but therapeutic efficacy decreases, even within the 3-hour window. To achieve optimal results, thrombolysis should be initiated as soon as possible after the onset of stroke.7 Thus, the ability to achieve rapid stroke onset-to-hospital and door-to-needle times will continue to play a key role in the management of acute stroke.
EVOLVING CRITERIA FOR PATIENT SELECTION
Appropriate patient selection is crucial-especially to prevent bleeding. Table 1 lists the current inclusion and exclusion criteria for thrombolysis in acute ischemic stroke. How to determine which patients are the best candidates for tPA treatment is a matter of ongoing investigation. In addition to time since symptom onset, other factors that appear to affect the risk/benefit ratio of thrombolysis for a particular patient include:
Extensive early ischemia. Whether patients with extensive early isch- emic 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 criterion currently required for intravenous tPA treatment (based on results of the NINDS trial) is the exclusion of ICH. A reevaluation of NINDS CT data showed no correlation between early infarct signs and either outcome or ICH rate.9
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 outcome10 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 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 CT should not be treated with tPA-even within the 3-hour window-because of the excessive risk of ICH.
Very mild or severe stroke. 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.12 However, precise clinical criteria for these exclusions have not been established.
Elevated blood glucose level. 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.13,14 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.15 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 intracerebral hemorrhage-regardless of tPA treatment.16 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 a value as close to normal as possible may be an optimal strategy. However, at this time there is no clear evidence to justify withholding tPA treatment because of hyperglycemia in patients who have acute ischemic stroke.
Implications of new imaging techniques for patient selection. 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:
New MRI sequences and modern CT techniques, such as CT angiography and perfusion CT, may have the potential to fulfill these criteria.
Diffusion MRI (DWI) (Figure) can delineate ischemic brain tissue within minutes of stroke onset, while perfusion 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.17
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 ther- apy appears to be safe and effective beyond a 3-hour window.18
Intra-arterial thrombolysis may offer the advantages of higher recanalization rates and shorter times to eventual recanalization.19,20 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.20 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 Prolysis in Acute Cerebral Thromboembolism (PROACT) trials I and II19 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. 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:
A pilot study that investigated the combination of lower-dose intravenous tPA given 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.21
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.22 The lytic agent desmoteplase (which has a longer half- life than tPA) is being 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. Ancrod, an enzyme that degrades fibrinogen, was tested in a series of clinical trials: there is evidence that ancrod may improve outcomes in patients treated within 3 hours of the onset of stroke.23
Platelet aggregation inhibitors. Two studies have shown that abciximab, a GIIb/IIIa receptor antagonist, has a reasonable safety profile and shows a trend toward benefit in treated patients.24 Combinations of tPA or reteplase and a GIIb/IIIa receptor antagonist (abciximab25 or integrilin26) used in intra-arterial therapy in small series of patients with acute ischemic stroke appeared to be safe. In 37 patients with severe stroke (average NIHSS score, 19), intravenous integrilin and intra-arterial tPA showed a trend toward better revascularization and clinical outcome compared with intra-arterial tPA alone.26
Endovascular interventional techniques. These include balloon angioplasty,22 mechanical removal of clots,27 laser-assisted thrombolysis of emboli, and use of ultrasound-assisted devices.28 All of these techniques are still in the experimental stage.
Multimodal approaches. Intravenous or intra-arterial administration of thrombolytic agents or GIIb/IIIa inhibitors has been used to enhance the effect of mechanical clot lysis.22,25 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.
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.29The 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. Table 2 lists the types of agents that have been evaluated in clinical trials as neuroprotective drugs. Unfortunately, so far none have demonstrated unequivocal efficacy, and none are currently approved for use in patients with stroke. However, many new trials of neuroprotective drugs are currently 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.30 Another approach to neuroprotection is to target multiple aspects of the ischemic cascade simultaneously.31 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 1 of these drugs would avoid many of the pitfalls associated with trials of unapproved drug combinations. However, none of these drugs have been studied in patients with acute ischemic stroke; they have only been suggested for study.
Neuroprotective drugs might also be used in combination with thrombolysis, and this strategy has the potential to provide maximum benefit. One way to do this would be to give a safe and effective neuroprotective drug before a patient's arrival at the hospital.32 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.33 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.
1. Marler JR, for the NINDS Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;24:1581-1587.
2. Fisher M, Brott TG. Emerging therapies for acute ischemic stroke: new therapies on trial. Stroke. 2003;34:362-364.
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. 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.
6. Wardlaw J, del Zoppo G, Yamaguchi T. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2000;(2):CD000213.
7. 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.
8. 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.
9. Patel SC, Levine SR, Tilley BC, et al, for the NINDS Study Group. Lack of clinical significance of early ischemic changes on computed tomography in acute stroke. JAMA. 2001;286:2830-2838.
10. 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.
11. von Kummer R, Allen KL, Holle R, et al. Acute stroke: usefulness of early CT findings before thrombolytic therapy. Radiology. 1997;205:327-333.
12. Hacke W, Kaste M, Olsen TS, et al, for the European Stroke Initiative Writing Committee. European Stroke Initiative (EUSI) recommendations for stroke management Eur J Neurol. 2000;7: 607-623.
13. Weir CJ, Murray GD, Dyker AG, Lees KR. Is hyperglycemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow-up study. BMJ. 1997;314:1303-1306.
14.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.
15.Demchuk AM, Tanne D, Hill MD, et al. Predictors of good outcome after intravenous tPA for acute ischemic stroke. Neurology. 2001;57:474-480.
16.Bruno A, Levine SR, Frankel MR, et al. Admis-sion glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology. 2002;59:669-674.
17. Schellinger PD, Fiebach JD, Hacke W. Imaging-based decision making in thrombolytic therapy for ischemic stroke: present status. Stroke. 2003;34: 575-583.
18. Rother J, Schellinger PD, Gass A, et al. Effect of intravenous thrombolysis on MRI parameters and functional outcome in acute stroke Stroke. 2002;33:2438-2445.
19. Furlan A, Higashida RT, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke: the PROACT II study: a randomized controlled trial: Prolysis in Acute Cerebral Thromboembolism. JAMA. 1999;282:2003-2011.
20.Schellinger PD, Fiebach JB, Mohr A, et al. Thrombolytic therapy for ischemic stroke-a review, part II: intra-arterial thrombolysis, vertebrobasilar stroke, phase IV trials, and stroke imaging. Crit Care Med. 2001;29:1819-1825.
21. Lewandowski CA, Frankel M, Tomsick TA, et al. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999;30:2598-2605.
22. Qureshi AI, Ali Z, Suri MF, et al. Intra-arterial third-generation recombinant tissue plasminogen activator (reteplase) for acute ischemic stroke. Neuro-surgery. 2001;49:41-50.
23. Sherman DG, Atkinson RP, Chippendale T, et al. Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA. 2000;283:2395-2403.
24. Adams HP, Bogousslavski J, Cook R, et al. The safety and efficacy of abciximab in acute ischemic stroke[abstract]. Ann Neurol. 2002;52:S64.
25. Qureshi AI, Suri MF, Khan J, et al. Abciximab as an adjunct to high-risk carotid or vertebrobasilar angioplasty: preliminary experience. Neurosurgery. 2000;46:1316-1325.
26. McDonald CT, O'Donnell J, Bemporad J, et al. The clinical utility of intravenous integrilin combined with intra-arterial tissue plasminogen activator in acute ischemic stroke. The MGH experience [abstract]. Stroke. 2002;33:S359.
27. Chopko BW, Kerber C, Wong W, Georgy B. Transcatheter snare removal of acute middle cerebral artery thrombembolism: technical case report. Neurosurgery. 2000;40:1529-1531.
28. Clark WM, Lutsep HL, Barnwell SL, et al. Multicenter feasibility study of an ultrasound drug infusion microcatheter for treatment of acute ischemic stroke [abstract]. Stroke. 2002;33: S359.
29. Hossmann K-A. Viability thresholds and the penumbra of focal ischemia. Ann Neurol. 1994;36: 557-565.
30.Ye ZR, Liu KF, Garcia JH. Mechanisms of neuronal cell death after ischemic brain injury. In: Fisher M, Bogousslausky J, eds. Current Review of Cerebrovascular Disease. 4th ed. Philadelphia: Current Medicine; 2001:15-24.
31.Fisher M, for the Stroke Therapy Academic Industry Roundtable. Recommendations for advancing development of acute stroke therapies: Stroke Therapy Academic Industry Roundtable 3. Stroke. 2003;34:1539-1546.
32. Saver JL, Kidwell CS, Hamilton S, et al. The Field Administration of Stroke Therapy-Magnesium (FAST-MAG) Phase 3 Trial. Ongoing Clinical Trials Session, 28th International Stroke Conference; February 13 - 15, 2003; Phoenix. Abstract CTP17.
33. Fisher M, Ratan R. New perspectives on developing acute stroke therapy. Ann Neurol. 2003;53:10-20.