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However, on the one hand, there is no study focusing on the direct comparison between streptokinase and alteplase, and on the other, streptokinase has not been adequately tested by dose ranging studies, unlike those of alteplase. Consequently, the common streptokinase dose, 1.

Recently, a new trial ATLANTIS Alteplase Thrombolysis of Acute Noninterventional Therapy in Ischemic Stroke , which was a placebo controlled, double bind pivotal study of the use of alteplase in patients with acute ischaemic stroke 3 to 5 hours from symptom onset, has been considered as a negative trial. The results of the PROACT-II study Prolyse in Acute Cerebral Thromboembolism Trial in which the dose of the pro-urokinase injected into the middle cerebral artery was 9 mg 6 mg pro-urokinase in the PROACT-I study showed significant clinical benefits of performing an intra-arterial thrombolysis in patients with an acute ischaemic stroke in the middle cerebral artery territory.

We think that thrombolysis is a potentially effective therapy for acute stroke 14 15 but additional information is necessary to establish how to select the best candidates for alteplase treatment before using it routinely, even within 3 hours of stroke onset. Despite numerous agents which can prevent the excitatory cascade of events leading to ischaemic neuronal death in experimental conditions, there is still no neuroprotective agent that has been shown conclusively to improve stroke outcome.

The first neuroprotective agent tested in stroke patients was nimodipine. This compound, a dihydropyridine, has been the most widely tested neuroprotector and provided no benefit in 15 trials 16 involving patients but a meta-analysis of the nine major nimodipine trials, 17 comprising patients, showed a significant improvement in functional outcome for those who received nimodipine within 12 hours of stroke onset.

This was suggested by an increased mortality, directly correlated with a fall in blood pressure. The second class of neuroprotective drugs is represented by the N-methyl-D-aspartate NMDA -receptor antagonists which inhibit the action of glutamate—the major excitatory neurotransmitter of the brain—excessively released from presynaptic neurons by ischaemic injury of the brain.

The NMDA receptor, a well characterised receptor mediated calcium channel, also contains glycine and polyamine modulatory sites that are potential therapeutic targets for neuroprotection. Glutamate antagonists share a propensity to cause psychotomimetic effects. A phase III trial is under way.

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Lubeluzole, a benzothiazole compound, is a sodium channel blocker that may inhibit the release of glutamate from ischaemic neurons, reducing postsynaptic excitotoxicity, 16 but it may act through other mechanisms as well, which include inhibition of glutamate induced nitric oxide NO related toxicity, with normalisation of peri-infarct neuronal excitability. Three phase 3 placebo controlled trials testing lubeluzole with mortality as the primary end point have been completed, including patients within 6 hours of stroke onset.

The European trial 27 was negative, whereas a non-significant trend for decreased mortality and a small significant effect on functional outcome was shown in the United States trial. A large phase III study to test the efficacy and safety of lubeluzole in the treatment of acute ischaemic stroke—with an 8 hour time window—has failed to show efficacy.

The rationale for using the antioxidants—free radical scavengers—is that ischaemia induces release of highly reactive oxygen free radicals, which are toxic to membranes. A 21aminosteroid tirilazad mesylate has free radical scavenging activity and antioxidant effects. Tirilazad has been evaluated in patients from six stroke trials. The most recent phase 3 trials with increased tirilazad dosage were stopped because of safety concerns or because they were unlikely to be of benefit. However, the differences were not significant.

Another potential neuroprotective agent is ebselen, a seleno-organic compound with antioxidant activity through a glutathione peroxidase-like action. Ebselen seems to increase the functional outcome but the improvement is significant only if the drug is received within 24 hours of stroke onset. Furthermore, data suggest that 5-clomethiazole is safe even in patients with haemorrhagic stroke. The results were negative, with worse outcome and increased mortality in the treatment group, in relation to increased infections and fever. In a phase 3 trial, 35 patients were randomised within 12 hours to piracetam 12 g as an initial intravenous bolus, 12 g daily for 4 weeks, and 4.

However, a trend toward improvement of the neurological score was found in the subgroup of patients randomised within 7 hours of onset, particularly in patients with stroke of moderate and severe degree. During ischaemia phosphatidylcholine is separated into free fatty acids, which can then generate free radicals that potentiate ischaemic injury.

Although it is often presented as a neuroprotector, it may rather act on recovery through delayed restorative mechanisms. Two trials, 36 37 one in patients, the other in patients, have triggered some interest in this drug, which showed no safety problem. The drug was given orally for several weeks within 24 hours of stroke onset, which clearly distinguishes these trials from usual acute stroke trials.

A significant improvement in functional outcome was claimed at 3 months in the treated group, but apparently this was the case only in subgroups of patients mainly the mg subgroup; moderate to severe strokes. Basic fibroblast growth factor bFGF , insulin-like growth factor, brain derived neurotrophic factor, and osteogenic protein 1 are among growth factors with a potential interest for stroke trials. In animal experiments, an improvement in outcome has been found even with delayed treatment 24 hours despite a lack of reduction of infarct size.

A recently completed phase 2 trial showed that bFGF was well tolerated by stroke patients but phase 3 trials have been interrupted for safety or concerns over lack of benefit. Magnesium may block the influx of calcium into ischaemic neurons. Although no randomised clinical trials of therapeutic hypothermia in acute ischaemic stroke have yet been announced to establish the efficacy and safety of this therapy, encouraging results have been recorded recently in acute traumatic brain injury.

In the interim between studies, some authors 45 think that available evidence is sufficient to recommend to maintain body temperature in a safe normothermic range In general, it is striking how drugs which have been shown to decrease significantly the size of infarct in animal models are not found to be clinically efficient in stroke patients. The discrepancy between experimental and clinical results for neuroprotective drugs may be due to several factors: Indeed, most of the earlier clinical trials were performed with a time window greater than 24 hours, which was most often arbitrarily fixed; even an efficient drug cannot possibly be demonstrated to have a positive effect under these conditions.

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Questions remain concerning the effective concentration of neuroprotective drug reached in the cerebral ischaemic infarct if the artery supplying this territory is occluded. We think that knowledge of the vascular status of the stroke patient is crucial to determine the best therapeutic strategy.

Another problem that may hamper our ability to achieve neuroprotection in stroke patients is a relative lack of understanding of specific pathophysiological issues of brain ischaemia in relation to the modes of action of specific drugs. For instance, antioxidants experimentally have an effect only in temporary focal ischaemia models, which suggests that their main clinical application would be in association with agents that facilitate reperfusion thrombolytic drugs. Also, certain classes of neuroprotective drugs, which act on specific synapses and receptors, may not work in white matter ischaemia, because these synapses and receptors may be malfunctional in such a situation or because these synapses and receptors—such as NMDA receptors—are lacking in the white matter.

Indeed, in stroke patients, glutamate seems to be a marker for cortical but not for deep hemispheric ischaemia. On the other hand, NMDA receptor antagonists may be particularly appropriate in patients in whom glutamate concentrations rise markedly, such as in progressive ischaemic stroke. Several critical issues remain unsettled for neuroprotection. Experimental studies demonstrated neuroprotective effects after focal cerebral ischemia.

A meta-analysis of patients suggested a positive effect on mild-moderate strokes, but no effect on severe strokes. Tirilazad mesylate, a aminosteroid, acts as a free radical scavenger and has antioxidant effects. Tirilazad treatment reduces infarct size after transient but not after permanent focal cerebral ischemia.

Tirilazad was tested in several clinical trials with inconclusive results. Aminoguanidines were reported to be potent neuroprotectants after focal cerebral ischemia. Another promising antioxidant is the seleno-organic compound ebselen.

Ebselen acts through a glutathione peroxidase—like effect. It inhibits the peroxidation of membrane phospholipids and lipoxygenase in the arachidonate cascade. Ebselen also blocks the production of superoxide anions by activated leukocytes, inhibits iNOS, and protects against peroxynitrite. Ebselen has been shown to be neuroprotective after transient and permanent experimental focal cerebral ischemia.

A significant reduction in infarct volume and outcome occurred only in the 6-hour subgroup. Monoclonal antibodies against the ICAM-1 receptor on the vascular endothelium prevent leukocyte activation and plugging. The ICAM-1 antibodies were shown to reduce infarct size and improve outcome after transient but not permanent experimental focal cerebral ischemia. The treatment group received IV mg the first day, 40 mg the next 4 days time window 6 hours , and had an even worse outcome and increased mortality due to higher rates of fever, infection, and pneumonia.

As indicated by preclinical studies, inhibition of these cytokines may have neuroprotective effects after cerebral ischemia. Recent trials of 3-hydroxymethylglutaryl coenzyme A reductase inhibitors statins demonstrated a significant reduction of ischemic stroke incidence in patients with history of coronary artery disease. Growth factors are endogenously occurring polypeptides that have not only neuroprotective but also regenerative and proliferative capacities and may therefore be unique candidates for stroke therapy.

Several growth factors were shown to be neuroprotective after experimental ischemia in vivo and in vitro. The best-studied growth factors after focal cerebral ischemia are basic fibroblast growth factor, brain-derived neurotrophic growth factor, insulin-like growth factor, and osteogenic protein Potential mechanisms of action after stroke include attenuation of excitotoxicity, improvement of cerebral blood flow, and reduction of apoptosis. Both compounds induced significant improvement of behavioral outcome without changes in infarct size when given 24 hours after ischemia.

Fibrinolytic Therapy in Acute Stroke

Citicoline reduces the size of infarction and improves neurologic outcome in experimental models of focal cerebral ischemia. The outcome based on the Barthel Index was significantly better only for the 0. Experimental studies demonstrated a neuroprotective and regenerative effect of piracetam after focal lesions. Only a subgroup of patients treated within 7 hours showed a trend toward better neurologic outcome. Amphetamines increase release at the noradrenergic terminals of norepinephrine, dopamine, and serotonin and could be future candidates for recovery studies after stroke. D-amphetamine improved behavioral outcome and memory function up to 60 days after focal cerebral ischemia.

This was correlated with enhanced neocortical sprouting and synaptogenesis in the group treated with D-amphetamine. Exploring effective combination therapies for stroke seems rational since cerebral ischemia triggers a multitude of pathophysiological and biochemical events that affect the evolution of focal ischemia differently.

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  • Impeding different steps in this cascade with different therapeutic agents may not only synergistically enhance the neuroprotective effect but may also allow the use of lower doses of each drug and consecutively less adverse effects. This approach demonstrated promise in several experimental studies and may serve as a future strategy for stroke therapy in humans. For example, combining low doses of citicoline with dizocilpine or basic fibroblast growth factor significantly reduces infarct size after focal cerebral ischemia, whereas a low dose of the compounds alone was not effective.

    Strategies include not only the combination of different neuroprotective agents but also the combination of thrombolysis and neuroprotection. However, more preclinical studies need to be completed before combination therapies should move into clinical development. The current status of acute stroke therapy can be appropriately described as a combination of "the best of times and the worst of times.

    The results of PROACT-2 demonstrate that successful treatment can be extended to selected patients within 6 hours of stroke onset given an intra-arterial thrombolytic agent. This news is countered by the current lack of documentation that any purported neuroprotective drug significantly improves outcome when given after stroke onset. In addition, the approved use of IV rt-PA is restricted to the United States and Canada, where only a very small percentage of stroke patients receive this intervention.

    Many lessons have been learned from the myriad successful and unsuccessful thrombolytic and neuroprotective trials, suggesting that future, better designed trials will likely demonstrate significant benefits with appropriate safe and effective drug treatments initiated within 6 hours of stroke onset.

    Also, the age of combination drug trials is approaching rapidly and it is combination treatments directed at both the vascular and cellular mechanisms of ischemic brain injury that are likely to have the greatest impact upon stroke disability. This is not a time to abandon hope for developing safe and effective stroke therapies that are beneficial when initiated hours after onset.

    Rather it is a time to reflect on lessons learned from recent scientific advances and clinical trials to better move forward into the new millennium. The acute treatment of ischemic stroke to improve neurologic and functional outcome remains a challenging task with the potential of tremendous rewards for both patients and the health care delivery system.

    Currently, the only approved therapy is IV tissue-type plasminogen activator initiated within 3 hours of stroke onset in appropriately selected patients. Intra-arterial infusion of another thrombolytic agent, prourokinase, within 6 hours of stroke onset also improved outcome in a single trial, but the drug has not yet been approved for general use. A large number of neuroprotective drugs were developed based on an enhanced comprehension of the mechanisms of focal ischemic brain injury.

    They were studied in pivotal clinical trials and so far there is no conclusive evidence of efficacy with any of these agents. It is hoped that effective neuroprotective therapy for acute ischemic stroke will be available soon and this therapeutic approach can then be combined with thrombolysis to enhance the benefits of acute stroke therapy. We thank Gregory W. Albers, MD, and Elaine J. Skalabrin, MD, for their helpful comments, and Linda M.

    Dickman for her secretarial support. N Engl J Med. Intravenous tissue plasminogen activator for acute ischemic stroke: Open label tissue plasminogen activator for stroke: J Stroke Cerebrovasc Dis. Intravenous rt-PA therapy for stroke in clinical practice: Early intravenous thrombolysis for acute ischemic stroke in a community-based approach. Intravenous tissue-type plasminogen activator for treatment of acute stroke: Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke ECASS II: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: Recombinant tissue-type plasminogen activator alteplase for ischemic stroke 3 to 5 hours after symptom onset: Thrombolysis in acute ischemic stroke: Prediction of stroke outcome with echoplanar perfusion- and diffusion-weighted MRI.

    Reversal of apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats. Thrombolytic reversal of acute human cerebral ischemic injury demonstrated by diffusion perfusion MRI [abstract]. Symptomatic intracranial haemorrhages occurred in All cause mortality was In summary, both devices MERCI retriever and Penumbra System can safely and effectively revascularize large intracranial vessels in patients experiencing ischemic stroke that present within 8 hours from symptoms onset although whether such revascularization leads to a better functional outcome compared to medical management alone has not been still demonstrated.

    A systematic review and meta-analysis of different studies in which mechanical thrombectomy with diverse devices have been used in the treatment of ischemic stroke was reported in [ 45 ]. The search yielded publications with included patients, but only were analyzed with a mean NIHSS score of Of 81 patients with concurrent thrombolysis, Compared with a matched cohort, patients who received mechanical intervention were There were no differences is the safety parameters between devices, except a trend to higher long-term functional independence with snare device.

    Endovascular therapy as a treatment of acute ischemic stroke is under incessantly investigation. Recent prospective clinical studies have shown that mechanical approaches combined with intra-arterial pharmacological therapy are associated with higher recanalization rates than either intervention alone However, the true effect on the clinical outcomes of these patients would only be elucidated through a randomized trial.

    This randomized trial funded by NINDS compares the mechanical approach with medical therapy in the 8-hour window from symptom onset. Participants are randomized to receive treatment either with the Merci Retriever and standard medical care or standard medical care alone clinicalTrials. The Ultrasound Thrombolytic Infusion Catheter combines the use of a distal ultrasound transducer with infusion of a thrombolytic agent through the micro catheter. In a pilot study, 14 patients with acute stroke 5 anterior circulation occlusions and 4 posterior circulation occlusions were treated with IA tPA or rateplase infusion through the EKOS micro catheter [ 49 ].

    Fibrinolytic Therapy in Acute Stroke

    No adverse events related to the catheter were registered. The experience is limited in other mechanical approaches. A few devices have been tested in clinical trials that had to be discontinued, some because of financial considerations and other for safety reasons.

    A number of mechanical thrombolysis devices such as Snarelike devices or Suction thrombectomy devices have not still been assessed in clinical trials. Anticoagulation as a secondary prevention treatment of cardioembolic stroke subtype has outstandingly reduced the annual risk of stroke in these patients and has completely changed their long-term survival [ 50 ]. However, acute cardioembolic stroke is associated with high morbidity and mortality since it usually causes a severe baseline neurological impairment, large infarct volumes and an increased risk of hemorrhagic transformation, above all when delayed spontaneous or pharmacological-induced arterial recanalization occurs [ 51 - 53 ].

    The rationale for thrombolysis for acute ischemic stroke is recanalization of occluded arteries to re-establish brain function by saving tissue at risk. The efficacy of IV thrombolysis has been established in non-selected patients because there was no interaction between tPA treatment and different baseline variables, suggesting a persistent beneficial effect of tPA across all subgroups of patients, even for all stroke subtypes [ 54 ].

    However, these IV thrombolysis clinical trials did not monitor presence and location of arterial occlusion and recanalization at different times after stroke. Arterial recanalization in acute stroke is associated with higher probability of long-term good outcome and lower probability of mortality [ 3 ]. Intravenous thrombolysis and pharmacological and mechanical intra-arterial thrombolysis have demonstrated to achieve higher and earlier vessel recanalization rates than spontaneous recanalization in acute stroke [ 32 , 55 , 56 ].

    Successful recanalization also depends on the site and extent of the thromboembolic occlusion being markedly lower in patients with intracranial internal carotid occlusion than in those with occlusions of the M1 or M2 segments of the middle cerebral artery [ 57 , 58 ].

    However, there are few data about the influence of the thromboembolus type on arterial recanalization and, in consequence, about the response to thrombolytic therapy among different stroke subtypes. Experimental studies have revealed that lytic susceptibility and penetration of thrombolytic agents into the thrombus depends on the specific structural aspects of clots.

    Old, platelet-rich, and well organized thrombi formed under flow conditions have been shown to be more resistant to thrombolysis than fresh, fibrin- and red cell-rich clots formed under conditions of stasis [ 59 , 60 ]. In humans, thromboembolic arterial occlusions may originate from various proximal sources, including venous sites, mural cardiac thrombi, or atherosclerotic lesions within or proximal to the affected vessel.

    Cardiac source of clot might probably represent the stroke subtype with more uniform fibrin-rich clots and higher efficacy of thrombolysis. A clinical study in 72 patients with proximal middle cerebral artery occlusion treated with IV tPA within 3 hours of onset showed a differential pattern of tPA-induced arterial recanalization among stroke subtypes [ 61 ]. Middle cerebral artery recanalization rate has been also confirmed to be higher in cardioembolic stroke in an intra-arterial thrombolysis clinical study in which 76 patients were treated within 6 hours of symptom onset [ 51 ].

    The trend to a higher rate of vessel recanalization in cardioembolic stroke with thrombolytic therapies might be as well explained for low plasma levels of endogenous tPA and its inhibitor plasminogen activator inhibitor-1 or PAI-1 since the raise of these markers have been related to increased risk of atherothrombotic ischemic events such as stroke or myocardial infarction [ 62 ].

    There are some studies that are not in line with a different pattern of recanalization according to stroke subtype. In a local intra-arterial thrombolysis study with UK in 62 patients with middle cerebral artery or intracranial internal carotid occlusion, only the thromboembolus location affected arterial recanalization. Neither stroke etiology nor other baseline parameters were related to successful recanalization [ 58 ].

    Importantly, within the group of cardioembolic occlusions, recanalization was significantly less when transoesophageal echocardiography showed a cardiac thrombus compared with those patients in which did not reveal the thrombus, probably explained by the different composition and age of the clot [ 58 ]. The embolic material is likely to be fibrin-rich in patients with atrial or ventricular thrombus, whereas in other conditions such as patent foramen ovale, right-to-left shunt, venous thrombi or recent onset of arrhythmia, clot is supposed to be fresher with higher content of platelets and red blood cells leading to an easier recanalization with thrombolytic therapies.

    In addition, cardioembolic and atherosclerotic sources of embolism had similar histological components with a high prevalence of a fibrin: Hence, it is controversial whether vessel recanalization with IV or endovascular thrombolytic therapies depends on the characteristics of the clot, and consequently, on the stroke subtype [ 51 , 58 , 61 , 63 , 64 ]. However, results of large clinical studies [ 64 ] and main randomized clinical trials of IV thrombolysis [ 4 , 5 , 54 ] have demonstrated no significant difference in final outcome in tPA-treated patients based on confirmed stroke mechanism.

    Since after tPA approval, treatment of acute ischemic stroke has totally changed. Intravenous thrombolysis has demonstrated to be safe and effective up to 4. Endovascular therapy in acute ischemic stroke has become a promising alternative for patients who are ineligible for intravenous thrombolysis or have failed in recanalyzing the occluded artery. Neurointerventional approaches in the treatment of acute ischemic stroke offer higher recanalization rates compared with intravenous thrombolysis but it is no clear whether improve outcomes. Randomized clinical trials are necessary to elucidate the true effect of endovascular thrombolysis on clinical outcomes.

    National Institutes of Health Stroke Scale. National Center for Biotechnology Information , U. Journal List Curr Cardiol Rev v. This is an open access article distributed under the terms of the Creative Commons Attribution License http: This article has been cited by other articles in PMC. Abstract Acute ischemic stroke is a major cause of morbidity and mortality in Europe, North America, and Asia. Thrombolysis, intra-arterial thrombolysis, mechanical thrombectomy, cardioembolic stroke, stroke subtype.

    Intravenous Thrombolysis with Alteplase 3 to 4. Open in a separate window.

    Thrombolytic Therapy in Patients With Acute Ischemic Stroke

    Heart disease and stroke statistics: Reasons for exclusion for thrombolytic therapy following acute ischemic stroke. The impact of recanalization on ischemic stroke outcome: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. Association of outcome with early stroke treatment: Good clinical outcome after ischemic stroke with successful revascularization is time-dependent. Perfusion CT in patients with acute ischemic stroke treated with intra-arterial thrombolysis: Safety and efficacy of ultrasound-enhanced thrombolysis: Ultrasound-enhanced thrombolysis for acute ischemic stroke.

    Thrombolysis with alteplase 3 to 4. Thrombolysis with alteplase