Thrombolytic Therapy for Acute Stroke (Current Clinical Neurology)
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In addition, the researchers in one of the trials have noted that the mortality rates for patients treated within a 3-hour time window were no different between the treated and placebo groups. They suggest further studies are warranted. Intra-arterial thrombolysis is an alternative approach to the use of IV thrombolytic therapy involving a cerebral angiogram to identify the site of occlusion, and delivery of thrombolytic therapy directly into the clot.
There have been 2 randomized, controlled trials of IA thrombolytic therapy for the treatment of stroke due to angiographically documented occlusion of the MCA.
Fibrinolytic Therapy in Acute Stroke
Both trials used recombinant prourokinase, a precursor of urokinase with high fibrin specificity ie, "clot specific" , administered within 6 hours of symptom onset. All patients received heparin calcium. Six patients were excluded after randomization but before treatment: Of the 40 patients treated, 26 received IA recombinant prourokinase 6 mg and 14 received IA placebo. Recanalization was augmented by the concomitant use of heparin, with higher doses of heparin opening up more arteries but lower doses of heparin resulting in fewer hemorrhagic complications.
Patients were stratified by enrollment NIHSS score into 1 of 3 severity categories , mild; , moderate to severe; and , severe to ensure a balance of stroke severity between the treated and placebo groups. The primary outcome measure was the mRS score at 90 days, with a favorable outcome defined as an mRS score of 2 or less. Patients with an intermediate severity stroke with an NIHSS score between 11 and 20 had the greatest difference in functional outcome between the recombinant prourokinase—treated group and the placebo group Table 4. In those patients with a mild stroke NIHSS score, , there was no difference in the proportion attaining a good functional status.
Recanalization rates were higher in the group treated with recombinant prourokinase but so were rates of symptomatic and asymptomatic hemorrhages. Despite the higher rate of early symptomatic hemorrhages in the recombinant prourokinase arm, mortality rates at 90 days were no different between the groups.
Intra-arterial thrombolysis was efficacious in patients with an angiographically documented MCA occlusion of less than 6 hours' duration. If some milder strokes improve without treatment, should we be treating such patients with thrombolytic agents? Thirty seven percent of all patients had minimal to no deficit at 3 months without any thrombolytic treatment; we do not know if the improvement was seen only in those with milder stroke. Are these patients with low NIHSS scores better candidates for IV recombinant tissue plasminogen activator therapy or should thrombolytic agents be avoided entirely?
To answer these questions, we need more studies to assess the benefits and risks of treatment according to the initial stroke severity. Patients with milder strokes who may do well without thrombolytic treatment should be able to weigh the chance of increased improvement with treatment vs the risk of worsening or dying from ICH. On the other hand, patients with severe strokes who may have an increased risk of hemorrhage from recombinant tissue plasminogen activator therapy may consider risking treatment to lessen the chance of being permanently disabled or dependent on others.
Like this trial by Adams et al, most stroke trials should be designed to randomize patients according to their initial stroke severity to help address the relation between initial stroke severity and impact of therapy. Being functionally independent is an excellent result for most patients with stroke who most fear their loss of independence.
Whereas full recovery is a laudable outcome, we may be striving for too much. Nevertheless, this was based on a small sample size insufficient for regulatory approval in the United States. Further work is needed to address patients' definition of quality of life so they can help us determine what outcome they most prefer. We advocate more outcome studies that address patient preferences, expanding on work done by Matchar and colleagues 17 that showed patients would rather be dead than dependent on others, so the added benefit of moving from an mRS score of 3 to 2 may be worthwhile to the patient population we are treating.
Based on the results of the NINDS trials, the Food and Drug Administration approved the use of IV recombinant tissue plasminogen activator therapy for the treatment of acute ischemic stroke in June Several studies 18 have since been published showing the safety and effectiveness of recombinant tissue plasminogen activator therapy in the community. The Standard Treatment with Alteplase to Reverse Stroke study 19 prospectively collected data on patients treated with recombinant tissue plasminogen activator from 24 academic and 33 community centers.
All principal investigators in this study were neurologists who had experience in treating patients with stroke who received recombinant tissue plasminogen activator. Tanne and colleagues 18 performed a retrospective survey of hospitals that have organized stroke triage systems and experience giving recombinant tissue plasminogen activator. Many of these reports published since approval of recombinant tissue plasminogen activator involved stroke centers experienced in the administration of thrombolytic agents. Many also used voluntary reporting of cases that may be biased.
The explanation for the higher rates of ICH and mortality is unknown. The researchers speculate that hospitals with less experience in the administration of recombinant tissue plasminogen activator may have had higher symptomatic hemorrhage rates. They also note that the high rate of departures from the national recommendations for treatment with recombinant tissue plasminogen activator may be a surrogate marker for lack of familiarity with thrombolysis and acute stroke management. Others 18 , 24 , 25 have also found higher complication rates when strict adherence to the guidelines was not followed, although the Standard Treatment with Alteplase to Reverse Stroke study 19 did not find a correlation.
These observations raise an important question of whether the community experience with recombinant tissue plasminogen activator can match that of a controlled trial run by experienced stroke investigators. More prospective studies will be needed to follow the outcome of patients treated with thrombolytic therapy outside of a randomized, controlled trial. These studies may also provide insight into other questions regarding widespread use of thrombolytic therapy.
Fibrinolytic Therapy in Acute Stroke
For instance, what is the appropriate level of clinical expertise needed for administration of thrombolytic therapy? Does a neurologist need to be present or simply available by telephone? On a larger scale, should thrombolytic treatment be available in all emergency department settings? These answers can only be provided by ongoing surveillance of recombinant tissue plasminogen activator use and carefully planned surveillance studies.
The Stroke Treatment in the Community project is still ongoing and, although this is a voluntary project with inherent biases, should provide important insights into the community experience with thrombolytic agents. Further analysis is under way to compare outcomes between patients treated at academic, metropolitan, and rural hospitals.
Another ongoing study 26 is a prospective comparison of the outcome of treatment with IV recombinant tissue plasminogen activator by emergency department physicians with telephone consultation of a neurologist vs treatment by a stroke neurologist. An educational program was supplied and the disparity lessened, but further results are pending. Extensive diagnostic testing may limit the application of recombinant tissue plasminogen activator because a certain level of expertise would need to be quickly available in all emergency departments.
Do we need to know the cause of stroke before we administer thrombolytic therapy? Since IV thrombolytic therapy must be administered within 3 hours of symptom onset, many patients receive treatment before the cause of stroke can be fully evaluated. Caplan et al 27 advocated using IV recombinant tissue plasminogen activator therapy only when arterial occlusive lesions can be demonstrated by vascular imaging studies. While this approach will treat only patients with ischemic stroke due to identifiable arterial blockage, it also delays treatment and limits thrombolytic intervention to specialized centers with readily available imaging technology.
Conversely, James Grotta, MD, recommends more widespread use of IV recombinant tissue plasminogen activator therapy for patients with acute ischemic stroke in strict accordance with published guidelines, emphasizing reducing time to treatment over establishing a definitive diagnosis. Both viewpoints illustrate the need for ongoing research to better define the indications for thrombolysis and identify new ones.
There are no recent, large, randomized, controlled studies that directly compare thrombolytic agents in the treatment of acute ischemic stroke. In the United States, IV recombinant tissue plasminogen activator therapy is the only approved agent for this indication. Based on recent controlled trials, streptokinase cannot be recommended for the treatment of ischemic stroke. Recent studies have demonstrated that IA prourokinase may be a new thrombolytic option in selected patients with stroke.
Although the recanalization rate for IA therapy is higher than that for IV administration, and recanalization is associated with improved outcome, until we have more conclusive evidence, we cannot recommend one route over the other. Studies need to be done that compare IA with IV therapy in patients with acute ischemic stroke. It is our opinion that IV recombinant tissue plasminogen activator therapy can at once be the standard of care for acute ischemic stroke and a source of comparison in prospective, randomized trials of new diagnostic and treatment alternatives.
For example, these trials may investigate the role of imaging technologies, such as diffusion-weighted magnetic resonance imaging, magnetic resonance angiography, CT angiography, and transcranial Doppler ultrasonography, in identifying optimal candidates for thrombolysis. Prospective, randomized trials using IV recombinant tissue plasminogen activator therapy as the standard of care also provide the most powerful and efficient means of investigating new treatment alternatives, such as variations in thrombolytic delivery dose, time window, mode of administration, and type of agent and combination therapy with cytoprotective agents or platelet inhibitors.
Thrombolytic Therapy in Patients With Acute Ischemic Stroke
In summary, thrombolytic therapy for ischemic stroke exemplifies the delicate balance between risk and benefit. Data from randomized, controlled trials have provided indications when the benefits of thrombolytic therapy clearly outweigh the risks. These trials also provide insight into clinical situations when the risk is too high for intervention. Unsettled issues requiring controlled investigation include the following: Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke.
Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. Other abbreviations are given in the legend to Figure 1. Fisher M, Schaebitz W. Copyright American Medical Association.
The effort to develop effective therapies for acute ischemic stroke achieved several important successes during the past decade, but also many disappointing failures. The 2 primary successes were related to thrombolysis. This study demonstrated that initiation of intravenous IV rt-PA within 3 hours after the onset of acute ischemic stroke significantly improved outcome at 3 months. The second major success was the demonstration that intra-arterial prourokinase initiated within 6 hours of stroke onset in patients with angiographically documented proximal middle cerebral artery MCA occlusion also improved outcome at 3 months.
These successful acute stroke therapy trials were outweighed by a large number of neuroprotective trial failures. Currently, not one of many purported neuroprotective therapies assessed in pivotal clinical trials has demonstrated unequivocal, statistically significant improvement in clinical outcome. In this overview of the current status and future direction of acute stroke therapy, we will discuss in detail the current situation of thrombolytic therapy for acute ischemic stroke, reviewing the results of published clinical trials, postmarketing experience with rt-PA given within the 3-hour window, and future directions of how to potentially expand this window for IV thrombolytic therapy.
The status of various neuroprotective therapies for acute ischemic stroke will be reviewed and potential new neuroprotective strategies previewed. Last, we attempt to envision likely approaches toward multiple therapeutic interventions, a treatment strategy likely to lead to maximal improvement in the greatest number of stroke patients. The NINDS rt-PA trial was the first acute ischemic stroke trial to unequivocally demonstrate that this disorder could be benefited by any therapeutic intervention.
Half of the patients were treated within 90 minutes of onset, an accomplishment by the investigators participating in the trial. The patients treated with rt-PA had a symptomatic intracerebral hemorrhage rate of 6. Subsequent analysis of the study data demonstrated that early computed tomographic CT demonstration of extensive edema or hypodensity, history of diabetes mellitus, and elevated baseline National Institutes of Health Stroke Scale Score NIHSS were predictors of poor outcome.
The initial analysis of the study data did not distinguish a difference in benefit of rt-PA related to time-of-treatment initiation. However, in a subsequent analysis that adjusted for baseline severity of the neurologic impairment, an earlier time to initiation of therapy was associated with a more favorable outcome, demonstrating an inverse linear relationship between time to treat and the odds ratio of a favorable outcome.
Several postmarketing studies of IV rt-PA are now available. The most important inclusion criterion was initiation of therapy within 3 hours of stroke onset. Most of the studies encompassed relatively small numbers of patients, ranging from 14 to 75 Table 1. These results must be interpreted cautiously because the baseline severity of the patients treated in these postmarketing studies were not as severe as in the NINDS trial.
The postmarketing studies do, however, provide some encouraging data about the rate of symptomatic intracerebral hemorrhage. It therefore appears that expanding IV rt-PA use into general practice is not associated with a substantially increased risk of intracerebral hemorrhage, if the guidelines for patient selection used in the NINDS trial are followed. Studies evaluating the efficacy of IV rt-PA beyond the 3-hour time window were conducted.
Predefined exclusion criteria included evidence of CT hypodensity or sulcal effacement involving more than a third of the MCA territory on the pretreatment CT scan. The overall results as analyzed in the intention-to-treat analysis of the trial were negative, but when protocol violators were excluded, several outcome measures were better in the rt-PA group.
In ECASS-2, the primary end point was the percentage of patients in the 2 treatment groups achieving a Rankin score of , and this outcome was observed in A post hoc analysis of the ECASS-2 data demonstrated a significant difference between the rt-PA—treated group and the placebo group when the Rankin score was dichotomized into 0 to 2 and greater than 2. In this analysis, The difference between a score of 1 or 2 on the Rankin scale is not great and this result speaks to the inherent difficulties in determining the best outcome measure to use in acute stroke studies.
In this study, the patients received 0. The trial included patients randomized 2: Secondary outcome measures also tended to be better in the r-proUK group.
Symptomatic intracerebral hemorrhage within 24 hours occurred in The PROACT-2 study demonstrates that thrombolytic therapy can be effective when initiated up to 6 hours after stroke onset in carefully selected patients and should initiate additional attempts to successfully expand the time window for IV thrombolysis in acute ischemic stroke.
How might the therapeutic time window for beneficial IV thrombolysis be expanded in acute ischemic stroke? There are at least 2 strategies possible that may be synergistic. The first strategy is better identification of patients likely to respond to treatment beyond 3 hours after stroke onset. In addition, angiography only provides information about the presence or absence of a vascular occlusion and does not provide information about the status of ischemic injury within the brain parenchyma.
The new magnetic resonance imaging MRI techniques of diffusion and perfusion MRI combined with magnetic resonance angiography can provide a wealth of information about the extent and location of ischemic injury and the status of perfusion in the microvasculature, and document the presence or absence of an occlusion in the major intracerebral vessels.
Preliminary evidence suggests that acute stroke patients who have perfusion lesion volumes larger than diffusion lesion volumes, so-called diffusion-perfusion mismatch have ischemic regions within the mismatch that are more likely to respond to therapeutic interventions such as thrombolysis. In 1 preliminary study, patients with a diffusion-perfusion mismatch who were successfully recanalized with IV rt-PA had a much better clinical outcome than patients who did not reperfuse.
Concerns arose that MRI may not accurately detect acute intracerebral hemorrhage. However, several recent reports document that susceptibility-weighted MRI studies can reliably demonstrate hemorrhages. A second potential approach to prolonging the therapeutic time window for successful thrombolysis would be to give neuroprotective therapy before, during, or after the infusion of IV rt-PA.
Neuroprotective therapy initiated before or during the use of IV rt-PA could extend the time that the ischemic penumbra, the presumed therapeutic target for both thrombolysis and neuroprotection, remains salvageable.
Another potential therapeutic combination would be the use of IV rt-PA followed by an agent designed to inhibit reperfusion injury induced by successful clot lysis. The possibility of secondarily generated reperfusion injury in the brain after clot lysis has been raised in the past without direct confirmatory evidence.
Recently, both animal and human MRI studies demonstrated that secondary injury after successful reperfusion does indeed occur, although the precise mechanisms responsible remain to be elucidated. It is quite possible that more than one of these potential inducers of secondary injury are active within different regions of the reperfused tissue. Prior animal studies demonstrated that drugs inhibiting polymorphonuclear leukocyte activity or free radical scavengers are almost exclusively beneficial in reperfusion models and demonstrate little if any effect in permanent occlusion models.
Neuroprotective agents and strategies have been studied for years and appear to be effective in a variety of preclinical stroke models. However, none of the drugs have proven conclusively to be effective in humans. It is difficult to translate data regarding drug dosage, time window, sex differences, and, in particular, the stroke target population from animals to humans.
Misunderstanding and misinterpretation of these issues may have caused negative trial results and a pessimistic view for neuroprotection of stroke in general. Evidence from the recent clinical trials demonstrates that subpopulations of stroke patients may benefit from the neuroprotective approach. It is hoped that the first neuroprotectant will be proven to be effective in the near future.
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Compared with thrombolysis, the neuroprotective approach for stroke treatment is more complex and reflects the diversity of the ischemic cascade Figure 1. Neuroprotective agents have been developed and tested for nearly all components of the ischemic cascade.
As seen with recently discovered mechanisms such as gene expression or the role of zinc after stroke, new agents may be developed and new therapeutic options occur. The discovery that calcium-induced excitotoxicity occurs after ischemia is relatively old about 20 years and was widely accepted as a key event after cerebral ischemia. Ischemia-induced energy failure causes membrane depolarization and release of excitatory amino acids such as glutamate into the extracellular space. Water, sodium, and chloride move intracellularly via monovalent ion channels into the cell causing so-called cytotoxic edema.
The large amount of intracellular clacium activates proteolytic enzymes that degradate cytoskeletal and extracellular matrix proteins. Calcium also activates phospholipase A2 and cyclooxygenase producing oxygen free radicals. The free radical release promotes further membrane damage, and subsequently mitochondrial dysfunction. Free radical activity can be blocked by antioxidants and free radical scavangers. Blocking of adhesion molecules can prevent these events. Activated inflammatory cells and injured neurons produce a number of toxic mediators that may worsen ischemia. Another mechanism that contributes to ischemic injury is apoptosis, although the role of apoptotic injury in stroke patients remains uncertain.
Triggered by a number of pathophysiological processes, including excitotoxicity, free radicals, the inflammatory reaction, and mitochondrial and DNA damage, apoptosis occurs after milder ischemic injury, particularly within the ischemic penumbra. Recovery and reorganization of the brain after focal ischemic injury occurs over weeks and may have a major impact on the outcome after stroke. Enhancement of recovery followed by improvement of behavioral outcome can be achieved in animals with drugs such as growth factors and amphetamines.
Various neuroprotective agents that may intervene on the ischemic cascade are presented in Figure 2. Calcium-channel antagonists were among the first drugs evaluated for neuroprotection after stroke. They reduce calcium influx into the cell via voltage-sensitive calcium channels. Calcium antagonists were indeed shown in several experimental studies to be neuroprotective after focal cerebral ischemia. Nimodipine was tested in at least 10 randomized, placebo-controlled stroke trials.
Aside from the positive results with reduction of mortality and improved neurologic outcome at 6 months after stroke in an early trial, all other trials had negative results. Nevertheless, nimodipine is standard treatment for prevention of ischemic neurologic deficits after subarachnoid hemorrhage. The NMDA antagonists reduce calcium influx into neurons through postsynaptic agonist-operated calcium channels.
Competitive NMDA antagonists such as phosphonates or selfotel block the glutamate recognition site of the receptor. Noncompetitive NMDA antagonists, including phencyclidine, ketamine, dizocilpine maleate, dextrorphan hydrochloride, and cerestat, block the NMDA-associated ion channel in a use-dependent manner. Negative modulation of receptor activity can be achieved by zinc and hydrogen.
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Magnesium blocks the channel in a voltage-dependent manner and has been shown to reduce infarct size after focal cerebral ischemia. Apart from the main recognition site for glutamate, the receptor also contains a glycine site and inhibition of the glycine action reduces NMDA receptor activity.
Antagonists of the glycine site of the receptor also reduce infarct size after experimental focal cerebral ischemia. Adverse effects occurred in a dose-dependent manner and included neuropsychiatric symptoms agitation, confusion, hallucination, catatonia, ataxia, dysarthria and hypertension. These adverse effects are known to be phencyclidine related and should not occur, when targeting another subunit of the NMDA receptor. A pilot study showed that the drug was well tolerated and associated with a trend toward fewer early deaths in a magnesium-treated group.
The main adverse events associated with clomethiazole use were somnolence and rhinitis. Based on these encouraging results, a second efficacy trial restricted to patients with large anterior circulation strokes was organized and will be completed soon. Lubeluzole, a benzothiazole compound, is a sodium blocker that prevents the presynaptic glutamate release and reduces postsynaptic excitotoxicity.
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.