New and Emerging Treatments for Acute Ischemic Stroke
The acute care of patients with stroke aims to control and prevent medical and neurological complications as well as reverse the neurological effects of the stroke itself. The most important advance is the hyperacute administration of r-TPA. A review of thrombolytic drugs and updated guidelines for their use in patients with stroke has recently been prepared.1 2
Recent Trials of Intravenous Thrombolysis
The results of five recent clinical trials of intravenous thrombolytic therapy for acute ischemic stroke are conflicting. A European trial using r-TPA showed benefit in a target subpopulation of patients but not for all patients treated, whereas an American trial of r-TPA yielded positive results. Three trials using streptokinase were prematurely terminated by safety committees concerned about high rates of acute mortality and intracranial bleeding. Differences in study results likely reflect different agents and dosages administered; severity of the stroke; different sites of occlusion; concomitant treatments, including aspirin; and more particularly, the time interval from stroke onset to treatment.
The results of the National Institute of Neurological Disorders and Stroke (NINDS) study showed that intravenous r-TPA significantly improved stroke outcomes at 3 months in carefully selected patients when administered within 3 hours of onset, following protocol requirements.1 2
Recent Studies of Intra-arterial Thrombolysis
Intra-arterial delivery of thrombolytic agents is an alternative to intravenous administration. Available evidence suggests that recanalization after intra-arterial delivery is in the range of 60% to 70%, which is superior to the 30% to 40% rate for intravenous delivery.3 Although these data encourage further testing of intra-arterial thrombolysis, the procedure should still be considered investigational, performed only by physicians who are experienced in neurointerventional techniques and in centers with neurological expertise.
Antithrombotic and Antiplatelet Aggregating Drugs
Although heparin is the most commonly prescribed antithrombotic drug, evidence about its safety and efficacy is limited. There are disagreements about the best level of anticoagulation, route of administration, timing and duration of treatment, use of bolus dose, severity of neurological deficits, size of infarction on baseline computed tomography (CT) that would contraindicate treatment, and the influence of either vascular distribution or presumed cause of stroke. Conclusive data are lacking about the ability of heparin to prevent early recurrent embolism among persons with presumed cardioembolic stroke.
Low-molecular-weight heparins and heparinoids have selective antithrombotic actions that may improve safety and reduce the risk of severe symptomatic autoimmune thrombocytopenia.
The immediate effects of 325 mg of aspirin on platelet aggregation suggest its usefulness in acute stroke. It is already part of the treatment for acute myocardial ischemia. Drugs such as anti-ICAM-1, which produces effects at the microvasculature level, are being tested.
Through effects at the cellular level, neuroprotective compounds are likely to reduce the severity of ischemic stroke. There is no convincing clinical evidence that any neuroprotective drug is effective in either reducing size of infarction or improving overall outcome.
Calcium Entry Antagonists
Early reports suggest that nimodipine provides improved outcome and reduced mortality in patients with stroke, although subsequent trials have not confirmed these results. A meta-analysis of nimodipine trials suggests a potential benefit if the drug is given within 12 hours of stroke onset. Additional studies of nimodipine given within 6 hours of onset are underway.
Experimental models of both transient and permanent focal brain ischemia suggest a benefit with either competitive or noncompetitive NMDA (N methyl-d aspartate) receptor antagonists, even when administered after onset of stroke. A major problem with the use of NMDA receptor antagonists in humans is the high rate of neuropsychiatric and hypotensive side effects. Trials of the noncompetitive antagonist cerestate and the polyamine antagonist eliprodil continue.
Sodium Channel Antagonists and Glycine Antagonists
Inhibition of presynaptic glutamate release by antagonists of the presynaptic sodium channels may be useful in stroke. A number of antiepileptic drugs, including phenytoin, fos-phenytoin, and lamotrigine have this property. Investigation of fos-phenytoin in human stroke is under way. A preliminary clinical trial has demonstrated a potential benefit from lubeluzole, and additional studies are ongoing.
Opioid antagonists may inhibit glutamate release in ischemic tissue. Small clinical studies of low-dose naloxone were equivocal. Nalmafene, an exomethylene derivative of naltrexone, has been tested for safety in patients with acute stroke, and a small placebo-controlled, dose-ranging study is nearing completion.
Antioxidants/Free Radical Scavengers
Generation of potentially toxic oxygen free radical species in ischemic brain tissue can lead to pathological lipid membrane peroxidation, with exacerbation of the ischemic cascade. Tirilazad mesylate, a 21-aminosteroid lipid peroxidation inhibitor, showed promise in experimental models in focal brain ischemia. Two large trials in Europe and North America were halted prematurely after interim analyses suggested a lack of efficacy. Further studies are testing higher doses.
Other agents that inhibit ischemic injury continue to be evaluated, including gangliosides, basic fibroblast growth factor, serotonin agonists, and citicoline.
Angioplasty and Stenting
Percutaneous transluminal angioplasty and intravascular stenting of the supra-aortic vessels are being examined for safety, feasibility, and long-term durability as an alternative to carotid endarterectomy and other revascularization procedures of the extracranial cerebral vessels.
Percutaneous transluminal angioplasty of intracranial vessels (carotid, middle cerebral artery stem, vertebral artery, and basilar artery) has been performed in a small number of symptomatic patients refractory to maximal medical treatment (blood pressure control, anticoagulants, and antiplatelet agents). While technically feasible, procedure-related stroke and death rates have been substantially higher than for patients undergoing extracranial procedures.
Neither angioplasty nor stenting of the extracranial or intracranial vasculature has been evaluated in clinical trials. Their use is considered investigational.
Healthcare System Issues of Dissemination and Implementation of Information
State-of-the-art acute stroke care delivery systems are relatively primitive compared with emergency trauma or cardiac care.
The same factors that lead patients to delay seeking medical assistance for acute myocardial infarction (AMI) also cause them to delay seeking medical help for stroke.
Attempts to influence such behavior have had limited success.
Medical System Factors
Prehospital evaluation and transport time account for significant delays in initiation of thrombolytic therapy for patients with AMI or acute stroke who require it. Aggressive stroke protocols and educational programs keyed to emergency medical services can markedly reduce the time from stroke onset to initiation of treatment.
An accurate diagnosis of stroke using a simplified prehospital stroke scale is feasible. Administration of thrombolytic therapy in acute stroke would be dangerous and is not likely to be advocated soon.
It is expedient to treat patients with intravenous thrombolytic agents in the emergency department (ED) before admission to the hospital. Treatment of acute stroke requires neurological expertise and the ability to read brain CT scans. Training in neurology and CT should be mandatory for emergency physicians and non-neurologists caring for patients with acute stroke. CT scanning must be available 24 hours a day in centers using thrombolysis.
Administrative and Triage Issues
Several novel approaches have been piloted in a few tertiary-level centers, with dramatic reductions in diagnostic and treatment delays. The use of one or more monitored beds in the ED dedicated to rapid evaluation and treatment of patients with suspected stroke has been reported. Brain resuscitation teams have also been modeled after the code Blue concept.
With high-risk therapies such as thrombolysis, many patients with acute stroke must be treated in an intensive care setting. The optimal structure and cost-effectiveness of such stroke units have not been well studied.
Emergency physicians receive no formal training in brain CT interpretation. Early signs of infarction and other CT diagnoses (eg, hemorrhagic infarction versus parenchymal hematoma) are easily missed, even by experienced investigators. Tele-medicine links could provide services for interpreting neuroimaging studies in outlying EDs.
The emergency physician can make the decision to administer thrombolytic therapy, but special training should be required for ED personnel, along with standardization of treatment and diagnostic protocols in conjunction with neurologists. Neurologists must also be available to the ED.
Drug Administration Issues
Stocking the thrombolytic drug in the ED instead of a central pharmacy significantly decreases delay to therapy.
The goal of future, well-controlled acute stroke trials is to expeditiously bring patients the most effective stroke therapy.
Patient Recruitment Issues
Acute Stroke Trials With Rapidly Changing Available Therapies
Past stroke trials have recruited patients for comparison of a therapeutic agent against placebo. A potential therapy must be compared with the best available therapy as defined by recent clinical trials. Multiple strategies are possible:
Alter trials of neuroprotective agents to recruit patients who are ineligible for current therapies.
Include best available therapy in both new treatment and placebo groups.
Remove best available therapy as an exclusion criterion in trials of new agents.
Compare new treatments with best available therapy.
Multiple Competing Studies
An attempt should be made to allow concurrent patient enrollment in multiple studies with a low likelihood of interfering with the primary outcome measure. Patients enrolled in studies of acute stroke therapy should not be excluded from studies of secondary stroke prevention.
Single Site With Multiple Concurrent Overlapping Studies
Investigators should look for complementary protocols so that most acute stroke patients arriving at their centers will be eligible for some study. This practice may induce bias unless the investigator uses a randomized permutated block design.
Functional scales (eg, the Barthel and Modified Rankin Scale) are essential for establishing a meaningful benefit to stroke patients and for procuring Food and Drug Administration approval of a new agent. The insensitivity of functional scales to the presence or absence of a neuroprotective action is due to the natural variability in stroke outcome, which is influenced by factors such as patient age, comorbid illness, size and location of infarct, previous infarct, and vascular pathology. In some cases, scores on functional scales may not parallel those on quality-of-life scales.
Neurological scales differ from functional scales in that certain aspects of the neurological disability (ie, motor, sensory, or cognitive) are arbitrarily assigned various weights. Neurological scales only crudely parallel changes in the complete neurological exam and cannot be considered linear measures.
Surrogate biological markers may help clarify the expected mechanism of action of drug agents and reinforce the primary end points. Methods such as perfusion magnetic resonance imaging (MRI), single-photon emission CT (SPECT) scan, or xenon CT can delineate ischemic regions and describe the region at risk. Diffusion-weighted imaging can delineate regions of the brain in which adenosine triphosphate levels have fallen and water has moved intracellularly so that it is less diffusible. This is an early stage of defining a region at risk of progression to infarction. Magnetic resonance angiography, perfusion MRI, and transcranial Doppler studies can also be used to assess the degree of reperfusion on repeat study.
A major cause of variability in outcome in large clinical trials has been the grouping of stroke patients with widely dissimilar sites of vascular occlusion. Surrogate markers can be used to target specific stroke subtypes for treatment or to test whether use of an agent has led to improved blood flow.
Time to Treatment
MRI data confirm that brain tissue in human stroke is frequently recruited into the volume of infarct over many hours. Considerable variation between individuals is likely, as is considerable variation between brain regions in a single individual, so the choice of a particular fixed time to treat is often too long for some and too short for others. The European r-TPA study indicates that in a clearly defined subgroup of patients, thrombolytic therapy up to 6 hours after onset significantly improves outcome.14 15 16 17
Evolution of Monotherapy to Multiple Concurrent or Sequential Therapies
The initiation and propagation of focal ischemic brain injury is a multifactorial process, representing a complex interplay between impairment of cerebral blood flow and the evolving metabolic consequences of the resulting ischemia. It is likely that therapies targeted at only one facet of this complicated process will be of only limited benefit.
The early initiation of neuroprotective drug therapy might be useful in that the time window for effective use of thrombolytic therapy is extended. Another approach would be to combine early thrombolytic therapy with interventions directed at the mechanisms of reperfusion injury: antioxidants or antiadhesion molecules. Other therapies, such as growth factors, inhibitors of apoptosis, nitric oxide modulators, adenosine modifiers, endothelin antagonists, and potassium channel agonists, are at earlier stages of investigation but might be more useful long range as multimodality therapy evolves.
Healthcare Charges and Reimbursement Issues
In some countries there is a strong tendency to charge all medical costs for treating a patient in a prospective clinical trial to the trial sponsor, even costs that are considered standard treatment and care. If this practice continues, the cost of performing any prospective trial may be prohibitive.
The American Heart Association should
Establish a multidisciplinary Acute Stroke Care Committee, similar to the Committee on Emergency Cardiac Care or the Committee on Trauma of the American College of Surgeons, to develop and promote strategies for acute stroke care to be implemented locally.
Emphasize that emergency treatment of stroke is part of a continuum of care that ranges from risk factor reduction and prevention to rehabilitation.
Help identify, endorse, educate, and support influential local stroke advocates and charge them with implementing strategies for acute stroke care.
Disseminate guidelines, consensus statements, and position papers related to acute stroke care to state and regional medical societies, hospital networks, and specialty organizations (eg, community stroke and emergency medicine societies) through local advocates.
Advocate reimbursement by payers of the usual and customary costs of medical care for patients participating in clinical research.
The AHA and other groups should
Increase awareness of the importance of early and successful treatment of persons with ischemic stroke to the following groups: the public, especially groups judged to be at the highest risk; physicians; other healthcare providers, including ED personnel; hospital administrators; third-party payers and care organizations; and government.
Develop educational programs on the emergency treatment of stroke with emphasis on the following: recognition of stroke, urgent transportation, emergency evaluation, general emergency treatment, and specific treatments for stroke.
Recent successful developments in acute stroke care are based on advances in basic and clinical research. Continued support and expansion of funding of stroke research by the National Institutes of Health, the AHA, and private sources is urgently needed. The AHA and its affiliates should
Expand funding of basic and clinical research in stroke.
Support research on new nonpharmacological interventions, particularly neurointerventional procedures.
Develop new mechanisms to facilitate and encourage applications from clinical and basic researchers.
Support research on outcomes after ischemic stroke.
Endorse the concept of acute treatment of stroke in specialized care facilities.
Support the funding of demonstration projects that examine the impact of acute stroke care delivery models on stroke outcome and costs.
†Dr Pessin died in 1996.
For reprint information, see page 1498.
- Copyright © 1997 by American Heart Association
Adams HP Jr, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Marler JR, Woolson RF, Zivin JA, Feinberg W, Mayberg M. 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.
Adams HP Jr, Brott TG, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Kwiatkowski T, Lyden PD, Marler JR, Torner J, Feinberg W, Mayberg M, Thies W. Guidelines for thrombolytic therapy for acute stroke: a supplement to the 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.. 1996;94:1167-1174.
Boysen G, Pessin MS. Thrombolytic therapy. In: Bogousslavsky J, Ginsberg M, eds. Cerebrovascular Disease: Pathology, Diagnosis, and Management. Malden, Mass: Blackwell Science; 1997.
Feinberg WM, Albers GW, Barnett HJM, Biller J, Caplan LR, Carter LP, Hart RG, Hobson RW II, Kronmal RA, Moore WS, Robertson JT. Guidelines for the management of transient ischemic attacks: from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks of the Stroke Council of the American Heart Association. Stroke. 1994;25:1320-1335.
Sherman DG, Dyken ML Jr, Gent M, Harrison JG, Hart RG, Mohr JP. Antithrombotic therapy for cerebrovascular disorders: an update. Chest. 1995;108(suppl):444S-456S.
Adams HP Jr, Woolson RF, Clarke WR, et al. Design of the trial of ORG 10172 in acute stroke treatment (TOAST): implications for other trials of treatments of persons with acute ischemic stroke. Control Clin Trials. 1996.
Higashida RT, Tasi FY, Halbach VV, Dowd CF, Hieshima GB. Transluminal angioplasty, thrombolysis, and stenting for extracranial and intracranial cerebral vascular disease. Journal of Interventional Cardiology. 1996;9. In press.
Rogers WJ, Bowlby LJ, Chandra NC, French WJ, Gore JM, Lambren CT, Rubison RM, Tiefenbrunn AJ, Weaver WD. Treatment of myocardial infarction in the United States (1990 to 1993): observations from the National Registry of Myocardial Infarction. Circulation. 1994;90:2103-2114.
Kereiakes DJ, Weaver WD, Anderson JL, Feldman T, Gibler B, Aufderheide T, Williams DO, Martin LH, Anderson LC, Martin JS, et al. Time delays in the diagnosis and treatment of acute myocardial infarction: a tale of eight cities. Report from the Pre-hospital Study Group and the Cincinnati Heart Project. Am Heart J. 1990;120:773-780.
Lyden PD, Rapp K, Babcock T, et al. Ultra-rapid identification, triage and enrollment of stroke patients into clinical trials. Journal of Stroke and Cerebrovascular Diseases. 1994;2:106-113.
Kothari R, Hall K, Broderick J, Brott T. Early stroke recognition: a prehospital stroke scale. Stroke.. 1996;27:171. Abstract.
Indredavik B, Bakke F, Solberg R, Rokseth R, Haaheim LL, Holme I. Benefit of a stroke unit: a randomized controlled trial. Stroke. 1991;22:1026-1031.
Adams RJ, Fisher M, Furlan AJ, del Zoppo G. Acute stroke treatment trials in the United States: rethinking strategies for success. Stroke.. 1995;26:2216-2218.
De Haan R, Horn J, Limburg M, Van Der Meulen J, Bossuyt P. A comparison of five stroke scales with measures of disability, handicap, and quality of life. Stroke. 1993;24:1178-1181.
Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemic stroke: challenging the concept of a rigid and universal time window. Stroke.. 1995;26:2219-2221.
Paczynski R, Hsu CY, Diringer MN. Pathophysiology of ischemic injury. In: Fisher M, ed. Stroke Therapy. Boston, Mass: Butterworth-Heinemann; 1995:29-64.