Hyperacute Therapy of Ischemic Stroke: Intravenous Thrombolysis

Hyperacute Therapy of Ischemic Stroke: Intravenous Thrombolysis

Hyperacute Therapy of Ischemic Stroke: Intravenous Thrombolysis Reza Jahan, MD Stroke is the third most common cause of death in the United States fol...

109KB Sizes 4 Downloads 94 Views

Hyperacute Therapy of Ischemic Stroke: Intravenous Thrombolysis Reza Jahan, MD Stroke is the third most common cause of death in the United States following heart disease and cancer. Following the success of thrombolysis for myocardial infarction in the early 1990s, major trials for evaluation of this new therapeutic approach for ischemic stroke were initiated. The majority of ischemic strokes are due to occlusion of a cerebral vessel by a blood clot. Occlusion of a cerebral blood vessel leads to a core of infracted tissue surrounded by a relatively hypoperfused but viable brain tissue (the ischemic penumbra), which can be potentially salvaged by rapid recanalization of the target vessel. The underlying rationale for introduction of thrombolytic drugs is the lysis of an obliterating thrombus and reestablishment of blood flow. In this article we review the major intravenous thrombolysis trials leading to approval of intravenous recombinant tissue plasminogen activator, the only FDA approved treatment available today for acute ischemic stroke. Tech Vasc Interventional Rad 8:81-86 © 2005 Elsevier Inc. All rights reserved. KEYWORDS stroke, intravenous, thrombolysis, trials


troke is a significant cause of morbidity and mortality in the industrialized nations of the world. It is the third most common cause of death in the United States following heart disease and cancer and the single most common reason for permanent disability.1 It is estimated that there are approximately 750,000 cases each year and over 150,000 deaths.2-6 The annual cost of stroke is estimated to be more than 30 billion dollars per year including medical costs, rehabilitation, and loss of employment.7,8 The majority of strokes are of the ischemic type and of those the majority are due to thromboembolic arterial occlusions.5,9 This is based on angiographic studies performed in stroke patients within 8 hours of symptom onset that show arterial occlusions corresponding to the symptoms in more than 80% of cases.10-12 An acute arterial occlusion rapidly produces a core of infarcted brain tissue surrounded by hypoxic but potentially salvageable tissue, ie, the ischemic penumbra.13-15 The ischemic penumbra is metabolically injured but capable of at least partial or perhaps complete functional recovery. The ischemic penumbral tissue is viable due to collateral blood flow and the time to irreversible injury is largely dependent on the degree of collateral flow. The molecular events initiated by focal ischemia include a time-dependent cascade characterized by decreased energy production, over-stimulation of neuronal glu-

Division of Interventional Neuroradiology, Department of Radiological Sciences, UCLA School of Medicine, Los Angeles, CA. Address reprint requests to Reza Jahan, MD, Division of Interventional Neuroradiology, Department of Radiological Sciences, UCLA School of Medicine, CHS Room B2-188, 10833 LeConte Ave., Los Angeles, CA 900951721. E-mail: [email protected]

1089-2516/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.tvir.2005.03.003

tamate receptors, excessive intracellular accumulation of sodium, chloride, and calcium, mitochondrial injury, and eventual cell death.16-19 The goal of thrombolytic therapy is rapid restoration of blood flow and preservation of the ischemic penumbra.20,21 The success of thrombolysis in acute myocardial infarction has generated great interest in cerebral fibrinolysis. Intravenous recombinant tissue plasminogen activator (t-PA) is now approved by the Food and Drug Administration (FDA) for the treatment of acute ischemic stroke within 3 hours of symptom onset.22 In this article we review the clinical trials in hyperacute intravenous thrombolytic therapy of ischemic stroke.

Intravenous Thrombolysis The two following thrombolytic agents have been utilized in intravenous trials of acute stroke treatment: streptokinase and t-PA.22-28

Intravenous Streptokinase Streptokinase was first reported in 1933 as a substance released by streptococci that dissolves blood clots.29 It has minimal enzymatic activity of its own until it combines with plasminogen leading to its activation to plasmin, a powerful fibrinolytic agent. One pilot study and three large randomized trials of intravenous streptokinase for treatment of acute stroke have been reported. In the pilot study, 20 patients were treated with 10 receiving streptokinase and 10 receiving placebo.30 Patients were treated within an average of 5.2 hours (placebo) and 5.8 hours (streptokinase) of stroke. There were three deaths in each group with three hemor81

R. Jahan

82 rhages in the treated group and one hemorrhage in the placebo group. The pilot study showed the feasibility of intravenous streptokinase in treatment of acute stroke and this led investigators to pursue large randomized trials evaluating streptokinase in acute ischemic stroke. The large randomized studies include the Multicenter Acute Stroke Trial-Europe (MASTE), The Multicenter Acute Stroke Trial-Italy (MAST-I), and the Australian Streptokinase Trial (ASK).23-25 As these studies were performed following the success of the thrombolytic trials for acute myocardial infarction (MI), the dose of streptokinase chosen in these trials was 1.5 million units, same as the dose given in the acute MI trials. The treatment was initiated within 4 hours in the Australian trial25 and within 6 hours in the other two.23,24 MAST-E23 randomized patients with carotid territory stroke. The primary efficacy endpoint was combined morbidity (Rankin ⱖ3) and mortality at 6 months. The primary safety outcomes were death at 10 days and intracranial hemorrhage (ICH). Due to an increase in mortality in the treated group, the trial was stopped after recruitment of 310 of the planned 600 patients. Mortality was 46.8% in the treated group versus 38.3% in the placebo group (P ⫽ 0.06). This difference in mortality was mainly due to fatal intracranial bleeding. MAST-I24 was a non-placebo-controlled randomized trial in which investigators attempted to determine the clinical benefits of streptokinase and aspirin alone or in combination for patients with acute ischemic stroke. A total of 622 patients were recruited with 157 patients receiving streptokinase, 153 receiving aspirin (300mg/day) for 10 days, 156 receiving both active treatments, and 156 receiving neither. Subcutaneous heparin was allowed but oral or intravenous anticoagulation and other antiplatelets were not allowed. The study was designed to recruit 500 patients in each subgroup but had to be stopped due to excessive mortality in the groups receiving streptokinase. The incidence of combined 6-month morbidity and mortality was reduced only slightly by streptokinase (odds ratio 0.9) and aspirin (odds ratio 0.9). ASK25 was a randomized, double-blind, placebo-controlled trial that administered streptokinase within 4 hours of stroke onset. Patients were followed for 3 months and additionally it prospectively compared patients randomized within 3 hours and those randomized within 3 to 4 hours. The safety committee stopped the trial after recruitment of 340 patients due to the poorer outcome in the 3- to 4-hour treated group. There were excessive deaths in the group treated after 3 hours (relative risk 1.98) but not among those treated within 3 hours (relative risk 1.11). There was a trend toward an unfavorable outcome in the streptokinase group versus placebo (48.3% versus 44.6%) and a higher rate of intracerebral hemorrhage in the treated group (13.2% versus 3%; P ⬍ 0.01). Thus each of the streptokinase trials was halted early due to poor outcome or an excess rate of mortality in the treated group of patients. These three negative studies make it unlikely that streptokinase will be used in the future in randomized trials for treatment of acute ischemic stroke. A metaanalysis of the streptokinase trials also failed to show a benefit of treatment.31 In a pooled analysis of the streptokinase trials there were 92 additional fatal intracranial bleeds per 1000

patients treated, with an odds ratio of 6.03.32 Several reasons can be cited for the failure of streptokinase in these clinical trials. First, the dose of streptokinase used was the full dose used in the coronary thrombolysis trials. Perhaps a lower dose of the drug would have been safer to use. In the successful National Institute of Neurological Disorders and Stroke (NINDS) intravenous t-PA trial,22 approximately two-thirds of the cardiac dose was used. Second, the patients were treated up to 4 and 6 hours after onset of symptoms. The Australian trial suggests that streptokinase may be effective if given within 3 hours of symptom onset. The number of patients treated within this time period was not large enough to show statistical significance. The third reason for failure of streptokinase may have to do with the use of antiplatelet and antithrombotic agents within the first 24 hours after treatment. In MAST-E for instance anticoagulation was given to 31% of the patients receiving streptokinase. In the placebo group only 12% received anticoagulation. This may have accounted for the difference in hemorrhage rate in the treated group in MAST-E. In the NINDS t-PA trial, antiplatelet and antithrombotic agents were avoided in the first 24 hours after administration of t-PA, perhaps leading to safer use of the thrombolytic drug. Additionally, streptokinase has undesirable side effects such as a decrease in systolic blood pressure as well as anaphylaxis. Based on the above-mentioned studies, the American Academy of Neurology recommendation regarding streptokinase in treatment of acute stroke was published in 1996.33 The recommendation states that, outside the setting of a clinical trial, streptokinase administration is not indicated for the management of patients with acute ischemic stroke.33

Intravenous t-PA rt-PA is produced endogenously by endothelial cells. Its action is similar to other thrombolytic drugs in that it is a plasminogen activator. It is fibrin specific as its activity is about three orders of magnitude greater in the presence of fibrin. This has the theoretical advantage of activating plasminogen bound to fibrin at the site of clot formation, reducing the chances of depleting circulating coagulation factors. rt-PA has been used in four phase 3 trials of acute ischemic stroke.22,26-28 FDA approval of t-PA was based on the NINDS t-PA trial.22 The study was composed of two clinical trials, Part I and Part II, with both trials conducted in identical fashion using the same inclusion and exclusion criteria.22 Altogether 624 patients were treated within 3 hours of symptom onset with a dose of 0.9 mg/kg t-PA, maximum dose 90 mg. Ten percent of the dose was given as a bolus with the rest given over 1 hour. Half the patients were treated within 90 minutes and the remainder from 91 to 180 minutes. A baseline CT scan was required to exclude ICH. Unlike other t-PA studies discussed below, there was no other CT exclusion criteria such as major early signs of infarction. Part I of the study evaluated early outcome. The primary hypothesis tested in Part I was that at 24 hours, compared with placebo, a greater proportion of patients treated with t-PA would improve by 4 or more points on the National Institutes of Health Stroke Scale (NIHSS). The median NIHSS at baseline was 14 (t-PA group) versus 15 (placebo group). Indeed 53% (76 of 144 patients) treated with t-PA had improvement by 4 or

Hyperacute therapy of ischemic stroke more points on the NIHSS compared with 39% (57 of 147) in the placebo group. Part II of the study then evaluated longterm functional outcome of patients at 3 months. The primary hypothesis tested in Part II was that there would be a significant difference in the t-PA and placebo group in the proportion of patients with minimal or no deficit. Four outcome scales were utilized for evaluation with minimal or no deficit defined as NIHSS of 0 or 1, Barthel Index (BI) greater than 95, modified Rankin Scale (mRS) of 0 or 1, and a Glascow Outcome Scale (GOS) of 1. For all four outcome measures, the t-PA-treated group fared better compared with the placebo. The t-PA patients were 32% (NIHSS), 38% (BI), 50% (mRS), and 55% (GOS) more likely to have a good outcome as defined above. The absolute percentage difference was 11 to 13% depending on the outcome measure being used. This means that for every 100 patients treated with t-PA, there would be an additional 11 to 13 patients with minimal or no deficit compared with 100 patients not treated with t-PA. The combined analysis of all 624 patients yielded the same results as Part II alone. The NINDS investigators have also reported follow-up on these patients up to 12 months.34,35 The odds ratio for a favorable outcome at 6 months was 1.7, 95% confidence interval (CI) 1.3 to 2.3, odds ratio at 12 months 1.7, 95% CI 1.2 to 2.3. The patients treated with t-PA were at least 30% more likely to have minimal or no deficit at 1-year follow-up. There was no significant difference in mortality at 12 months between the two groups (24% versus 28%, P ⫽ 0.29). The rate of recurrent stroke at 1 year was similar in the two groups. The results indicate a sustained benefit of t-PA at 12 months. Outcome did not vary by stroke subtype at baseline. This means that patients with small vessel disease were as likely to benefit as patients with, for instance, cardioembolic stroke. One point must be made here, however, that the determination of stroke subtype was based purely on clinical examination and not on angiographic or magnetic resonance imaging (MRI). Overall, 6% of the patients receiving t-PA had symptomatic ICH compared with 0.6% in the placebo group. Despite the higher rate of symptomatic ICH in the t-PA group, there was no significant difference in mortality between the two groups. Several explanations have been proposed to explain these contradictory findings.36 On the one hand t-PA may have decreased mortality by reducing the size of infarction and hence reducing the likelihood of death in these patients. Second, the patients that had symptomatic ICH had large infarction that even without hemorrhage would have had high associated mortality. In other words, in the t-PA group patients with large infarctions died with hemorrhagic transformation, while in the placebo group these same patients died but without hemorrhagic transformation. Thus we see a higher rate of symptomatic ICH in the t-PA group but with no significant difference in mortality between the two groups. The NINDS investigators sought to identify variables associated with hemorrhage in patients that received t-PA.37 The investigators identified 45 variables from 35 baseline measures to test for an association with symptomatic ICH and all ICHs within 36 hours of treatment. The risk of symptomatic ICH was increased in the presence of a severe neurological deficit (NIHSS ⬎20 at baseline) and clear signs of brain edema (defined as acute hypodensity) or mass effect on the pretreatment CT scan. However, despite this, in both sub-

83 groups of patients, treatment with t-PA was more likely to result in an excellent neurological outcome at 3 months. The likelihood of severe disability or death was the same in these patients in both the t-PA and the placebo group. The investigators thus concluded that, despite a higher rate of symptomatic ICH, patients with severe stroke or edema or mass effect on pretreatment CT are reasonable candidates for t-PA, if it is administered within 3 hours of symptom onset.37 The NINDS investigators also performed subgroup analysis to identify stroke patients in whom treatment with t-PA was particularly hazardous or efficacious.38 Historical, physical, and laboratory findings that could easily be identified before treatment were correlated to outcome. The study concluded that no pretreatment information significantly affected outcome in patients treated with t-PA. Note should be made that there was no association between age and benefit from t-PA. Although older patients did not do as well as younger patients, older patients that received t-PA did better than older patients that did not receive t-PA. Three additional phase 3 trials with IV t-PA have been reported all with negative results. These include the European Cooperative Acute Stroke Study (ECASS), ECASS II, and Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS).26-28 ECASS was a prospective, multicenter, double-blind, placebo-controlled study.26 It differed from the NINDS study in several important aspects. First, the dose of t-PA in ECASS was 1.1 mg/kg with a maximum dose of 100 mg versus NINDS where 0.9 mg/kg was used with maximum dose of 90 mg. Second, patients were treated up to 6 hours after onset of symptoms versus NINDS where recruitment was up to 3 hours post symptom onset. Finally, patients with major early signs of ischemia on CT scan were excluded from the study. There was no CT exclusion criteria in the NINDS trial other than hemorrhage. A major sign of ischemia on CT scan was defined as hypodensity involving more than one-third of the MCA territory. Anticoagulation and neuroprotective agents were not permitted. The primary treatment endpoint included BI and mRS at 90 days. In the intent to treat (ITT) analysis, there was no significant difference in either of the two primary endpoints between the two groups of patients. This was thought to be due to the fact that a significant number of patients included in the analysis had protocol violations. To address this issue further, an analysis of the target population (TP) was also performed by excluding 109 patients that were included in the trial but were found later to have protocol violations. Analysis of the TP revealed no significant difference in the BI between the two groups but significant difference in the mRS in favor of the t-PA-treated patients. Of the 109 that were excluded from the TP analysis, 66 were because of abnormalities on CT scan (52 had major early infarction signs, 2 had a primary hemorrhage, 12 had unavailable or unreadable CT). The investigators concluded that t-PA is beneficial in improving some functional outcomes in a subgroup of patients with moderate to severe neurologic deficits and without extended signs of ischemia on the initial CT scan. However, identification of this subgroup of patients is difficult and largely depends on identification of early signs of infarct on CT scans. Furthermore, treating ineligible patients is associated with an unacceptable risk of hemorrhage and death. Therefore, IV t-PA

R. Jahan

84 administration within 6 hours of symptom onset cannot be recommended. Interestingly, a post-hoc analysis of the ECASS 3-hour cohort (n ⫽ 87) did not reveal a significant difference between the rt-PA and placebo group outcomes. In ECASS, there was no significant difference in occurrence of hemorrhages in the t-PA or placebo group in either ITT or TP analysis. However, large parenchymal hemorrhages were more frequent in the t-PA-treated group. ECASS II was designed therefore with a lower dose of t-PA (0.9 mg/kg chosen to match NINDS criteria) given intravenously within 6 hours of symptom onset. The primary endpoint was the mRS at 90 days. A total of 800 patients (409 rt-PA, 391 placebo) were randomized. The safety analysis showed similar mortality in the two groups (10.5% versus 10.7%). On the one hand there was a substantially increased number of fatal intracranial hemorrhages in the rt-PA group (11 versus 2 patients), whereas more patients died of space occupying cerebral edema in the placebo group (8 versus 17 patients). Overall symptomatic ICH occurred in 36 (8.8%) rt-PA patients and 13 (3.4%) placebo-treated patients. The investigators found no significant difference in the primary endpoint between the t-PA and placebo groups (mRS ⱕ1: 40% versus 37%; P ⫽ 0.277). The results did not confirm a statistical benefit for the lower dose rt-PA administered within 6 hours of symptom onset. Similar to ECASS I, the 0- to 3-hour cohort did not show a significant benefit for rt-PA. The approved use of rt-PA remained restricted to patients presenting within 3 hours of symptom onset. This however severely restricted the use of the drug as evidenced by data showing that since approval of the drug less than 5% of all stroke patients were receiving rt-PA.28,39,40 Therefore the ATLANTIS trial assessed the safety and efficacy of rt-PA (0.9 mg/kg with maximum dose of 90 mg as in NINDS trial) in patients 3 to 5 hours post symptom onset. In actuality the study began in 1991, designed to test safety and efficacy of rt-PA within 6 hours of symptom onset. In 1993, due to safety concerns, the time window was changed to 0 to 5 hours. This was further modified in 1996 after the FDA approval of rt-PA to 3- to 5-hour time window. ATLANTIS was designed as a phase 3, placebo-controlled, double-blind randomized study. Primary efficacy was an excellent neurologic recovery at day 90 (NIHSS less than or equal to 1). In the target population 32% of the placebo and 34% of the t-PA patients had an excellent recovery at 90 days (P ⫽ 0.65). There was a significant increase in occurrence of symptomatic ICH in the t-PA group (1.1% versus 7.0%; P ⬍ 0.001). The study did not show a significant benefit of t-PA in patients treated between 3 to 5 hours post ictus. The recommendations of the American Academy of Neurology regarding intravenous t-PA are that administration of this drug within 3 hours of symptoms is indicated in patients meeting the inclusion and exclusion criteria as set forth by the NINDS t-PA trial.33 Intravenous administration of t-PA for a patient who has had a stroke greater than 3 hours cannot be recommended. Despite approval of t-PA for treatment of acute ischemic stroke, there has been much trepidation about its use. It is estimated that 1% of all ischemic stroke patients and 2% of patients eligible for IV rt-PA (presenting within the 3-hour time window) receive the drug. The work-up of patients with stroke is rapidly performed with no pathophysiologic

work-up done to document the presence of an occlusive clot. Many with symptoms of acute ischemic stroke may not have occlusive thromboemboli41 leading to erroneous administration of a potentially dangerous drug to patients that lack the target lesion the drug is intended to treat. The drug will be less efficacious under these circumstances compared with the idealized conditions under which the trial was performed. Additionally, concern is raised over the use of the drug in general community practice. The Standard Treatment with Alteplase to Reverse Stroke Study (STARS) addressed the latter concern over the use of t-PA in the community.42 This prospective multicenter study reported the results of intravenous t-PA treatment of patients with acute ischemic stroke in 57 medical centers in the United States (24 academic and 33 community). The study confirmed the beneficial effects of t-PA administered within 3 hours of symptom onset with results similar to those obtained in the NINDS trial. Conflicting results however were found by Katzan and coworkers.43 These authors reported results of stroke patients treated with IV t-PA in essentially all the hospitals in Cleveland, Ohio. A large percentage of patients in the study had deviations from national treatment guidelines. In addition, the study showed a significantly higher rate of symptomatic ICH and mortality in patients receiving the drug. Blood pressure guidelines were followed in only 48% of the patients and baseline NIHSS was documented in 40% of the patients. These facts illustrate the point that IV thrombolysis should be performed in centers that are experienced. In fact it was encouraging that evidence of a t-PA learning curve was found in the Cleveland experience. There was a downward trend in the occurrence of guideline deviations and an increase in the rate of IV t-PA use over time.43

Abciximab in Acute Ischemic Stroke Although IV t-PA has been shown to be efficacious in treatment of acute ischemic stroke, its use is limited due to the short time window of 3 hours from ictus. More recently clinical trials have shown a modest benefit of aspirin if started within 48 hours of stroke onset.44,45 These studies raise the possibility that a more potent antiplatelet agent may be more effective if started within a few hours of stroke onset. Abciximab is the Fab fragment of a chimeric human/mouse monoclonal antibody directed against the platelet glycoprotein IIb/ IIIa (GP IIb/IIIa) receptor, a mediator of aggregation.46 Abciximab is currently approved in combination with aspirin or heparin for prevention of ischemic complications in patients undergoing percutaneous coronary interventions.47-50 The regimen for infusion of Abciximab consists of a bolus dose of 0.25 mg/kg followed by a continuous infusion of 125 ␮g/kg/min (maximum dose 10 ␮g/min). This causes an 80% blockade of the GP IIb/IIIa receptors with prolongation of bleeding time to more than 30 minutes.51,52 The antiplatelet activity of Abciximab persists for 4 to 6 hours after termination of IV infusion, with platelet function gradually recovering over the next 24 to 48 hours.51,52 In view of the success of Abciximab in treatment of acute coronary artery lesions, interest has grown over the use of the drug for acute ischemic stroke. The Abciximab in Ischemic Stroke Investigators per-

Hyperacute therapy of ischemic stroke formed a randomized, double-blind, placebo-controlled, dose escalation study of Abciximab in acute ischemic stroke.53 The primary objective of the study was to evaluate the risk of major intracranial bleeding within 5 days after treatment. The study population consisted of adult patients with acute ischemic stroke presenting within 24 hours of symptom onset. All patients had a head CT and had a minimum NIHSS of 4. Four doses of Abciximab were evaluated against placebo in a dose-escalating sequence with a ratio of 3:1 treatment versus placebo. The escalating dosing regimen consisted of (1) 0.15 mg/kg bolus increasing to (2) 0.20 mg/kg bolus followed by (3) 0.20 mg/kg bolus and infusion and finally escalating to (4) 0.25 mg/kg bolus and infusion. The infusion dose consisted of 0.125 ␮g/kg/min, same as that used in the cardiac intervention trials. Before any dose escalation was performed, all patients in a particular dose tier had to be enrolled. If the drug was deemed safe in the lower dose, then escalation to the next dose tier was performed. Twentyseven of 38 participating sites enrolled 74 study patients with 20 patients assigned to placebo. The median time from stroke onset in all patients was 12 hours (range, 2 to 23 hours) and the median baseline NIHSS was 15 (range, 4 to 25). There were no cases of fatal or nonfatal ICH within 5 days of treatment or within 3 months after randomization. Asymptomatic ICH was detected overall in 10 of 54 (19%) Abciximab patients and in 1 of 20 (5%) placebo patients through 3 months. Of the asymptomatic bleeds, five occurred at the 0.25 mg/kg bolus plus infusion dose. Systemic bleeding occurred in 10 (10/54; 19%) treated patients and in 4 (4/20; 20%) placebo patients. None of these hemorrhages were major. Four of the treated patients (4/54; 7%) had moderate thrombocytopenia during the first 5 days after treatment. There were no cases of severe thrombocytopenia. In evaluation of efficacy, there was no difference in overall neurological improvement at day 5 and at 3 months. There was no difference in stroke progression during the first 5 days or in stroke recurrence during the first 3 months. However, differences were noted in functional outcome at 3 months. Nineteen of 54 (35%) Abciximab patients and 4 of 20 (20%) placebo patients had minimal disability (modified Rankin Score ⱕ1) at 3 months. This was the first study to evaluate Abciximab in the treatment of acute ischemic stroke. The absence of major ICH is encouraging. The excess of asymptomatic bleeds in the Abciximab group may be due to the fact that a larger proportion of these patients underwent unscheduled brain imaging studies. The proportion of patients with minimal disability at 90 days was higher in the treated group. The results suggest that Abciximab deserves further evaluation for this purpose. Currently, additional studies to evaluate Abciximab in the treatment of acute ischemic stroke within 6 hours of ictus is underway.

Conclusion In conclusion intravenous rt-PA should be performed within 3 hours of symptom onset in centers experienced with the procedure. The randomized trials have shown that the benefit of rt-PA beyond 3 hours is lower, but definitely present in selected patients. However, identification of this population is difficult and may lead to erroneous administration of rt-PA

85 to ineligible patients with unacceptable rates of fatal hemorrhage. Intravenous administration of streptokinase is dangerous and not indicated outside the setting of a clinical trial. Data on the efficacy of any other thrombolytic drug are not available and no recommendations are made with regard to this. The benefits of recanalization may be supplemented with neuroprotective drugs, particularly when the two are used simultaneously and very early after stroke onset. Finally, preliminary results in the use of platelet glycoprotein IIb/IIIa antagonists in treatment of acute ischemic stroke appear encouraging. Additional studies to define the role of this class of agents in treatment of this disorder are underway.

References 1. WHO Task Force: Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and Other Cerebrovascular Disorders. Stroke 20:1407-1431, 1989 2. Wolf PA, Kannel WB, McGee DL: Epidemiology of strokes in North America, in Barnett HJM, Stein BM, Mohr JP, et al (eds): Stroke: Pathophysiology, Diagnosis and Management. New York, NY, Churchill Livingstone, 1986, pp 19-29. 3. Chambers BR, Norris JW, Shurvell BL, et al: Prognosis of acute stroke. Neurology 37:221-225, 1987 4. Broderick J, Brott T, Kothari R, et al: The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke 29:415-421, 1998 5. Feussner JR, Matchar DB: When and how to study the carotids. Ann Intern Med 109:805-818, 1988 6. Thorvaldsen P, Kuulasmaa K, Rajakangas AM, et al: Stroke trends in the WHO MONICA project. Stroke 28:500-506, 1997 7. Barnaby W: Stroke intervention. Emerg Med Clin North Am 8:267281, 1990 8. Dobbin B: The economic impact of stroke. Neurology 45:S10-S14, 1995 (suppl 1) 9. Zeumer H, Freitag HJ, Knospe V: Intravascular thrombolysis in central nervous system cerebrovascular disease. Neurol Clin North Am 2:359369, 1992 10. del Zoppo GJ, Poeck K, Pessin M, et al: Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 32:78-86, 1992 11. del Zoppo GJ, Higashida RT, Furlan AJ, et al: PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke 29:4-11, 1998 12. Furlan A, Higashida R, Wechsler L, et al: Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 282:20032011, 1999 13. Baron J: Mapping the ischaemic penumbra with PET: implications for acute stroke treatment. Cerebrovasc Dis 9:193-201, 1999 14. Heiss WD, Thiel A, Grond M, et al: Which targets are relevant for therapy of acute ischemic stroke? Stroke 30:1486-1489, 1999 15. Nagesh V, Welch KM, Windham JP, et al: Time course of ADC changes in ischemic stroke: beyond the human eye. Stroke 29:1778-1782, 1998 16. Zivin JA: Factors determining the therapeutic window for stroke. Neurology 50:599-603, 1998 17. Rosenblum WI: Histopathologic clues to the pathways of neuronal death following ischemia. J Neurotrauma 14:313-326, 1997 18. Lee JM, Zipfel GJ, Choi DW: The changing landscape of ischemic brain injury mechanisms. Nature 399:A7-A14, 1999 (suppl) 19. Kristian T, Siesjo BK: Calcium in ischemic cell death. Stroke 29:705718, 1998 20. Hacke W, Stingele R, Steiner T, et al: Critical care of acute ischemic stroke. Intensive Care Med 21:856-862, 1995 21. Astrup J, Siesjo B, Symon L: Thresholds in cerebral ischemia—the ischemic penumbra. Stroke 12:723-725, 1981 22. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581-1587, 1995 23. The Multicenter Acute Stroke Trial-Europe Study Group: Thrombo-

R. Jahan







29. 30. 31.



34. 35.

36. 37.


lytic therapy with streptokinase in acute ischemic stroke. N Eng J Med 335:145-150, 1996 Multicentre Acute Stroke Trial-Italy (MAST-I) Group: Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 346:1509-1514, 1995 Donnan GA, Davis SM, Chambers BR, et al: Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 276:961-966, 1996 Hacke W, Kaste M, Fieschi C, et al: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 274:1017-1025, 1995 Hacke W, Kaste M, Fieschi C, et al: Randomised double-blind placebocontrolled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 352:1245-1251, 1998 Clark WM, Wissman S, Albers GW, et al: Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 282:2019-2026, 1999 Tillet WS, Garner RL: The fibrinolytic activity of hemolytic streptococci. J Exp Med 58:485-502, 1933 Morris AD, Ritchie C, Grosset DG, et al: A pilot study of streptokinase for acute cerebral infarction. QJM 88:727-731, 1995 Cornu C, Boutitie F, Candelise L, et al: Streptokinase in acute ischemic stroke: an individual patient data metaanalysis: the Thrombolysis in Acute Stroke Pooling Project. Stroke 31:1555-1560, 2000 Wardlaw JM, del Zoppo GJ, Yamaguchi T: Thrombolysis for acute ischemic stroke (Cochrane Review). Cochrane Database Syst Rev 2:CD000213, 2000 Report of the Quality Standards Subcommittee of the American Academy of Neurology: Practice advisory: thrombolytic therapy for acute ischemic stroke-summary statement. Neurology 47:835-839, 1996 Kwiatkowski TG, Libman R, Frankel M, et al: The NINDS rt-PA Stroke Study: sustained benefit at one year. Stroke 29:288, 1998 Kwiatkowski TG, Libman RB, Frankel M, et al: Effects of tissue plasminogen activator for acute ischemic stroke at one year. National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. N Eng J Med 340:1781-1787, 1999 Broderick JP: Recanalization therapies for acute ischemic stroke. Semin Neurol 18:471-484, 1998 The NINDS t-PA Stroke Study Group: Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 28:2109-2118, 1997 The NINDS t-PA Stroke Study Group: Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke 28:2119-2125, 1997

39. Chiu D, Krieger D, Villar-Cordova C, et al: Intravenous tissue plasminogen activator for acute ischemic stroke: feasibility, safety, and efficacy in the first year of clinical practice. Stroke 29:18-22, 1998 40. Tanne D, Bates VE, Verro P, et al: Initial clinical experience with IV tissue plasminogen activator for acute ischemic stroke: a multicenter survey. The t-PA Stroke Survey Group. Neurology 53:424-427, 1999 41. Libman RB, Wirkowski E, Alvir J, et al: Conditions that mimic stroke in the emergency department. Implications for acute stroke trials. Arch Neurol 52:1119-1122, 1995 42. Albers GW, Bates VE, Clark WM, et al: Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA 283:11451150, 2000 43. Katzan IL, Furlan AJ, Lloyd LE, et al: Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 283:1151-1158, 2000 44. CAST (Chinese Acute Stroke Trial) Collaborative Group: CAST: randomized placebo-controlled trial of early aspirin use in 20 000 patients with acute ischemic stroke. Lancet 349:1641-1649, 1997 45. Sandercock P: for the International Stroke Trial Collaborative Group: The international Stroke trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke. Lancet 349:1569-1581, 1997 46. Chong PH: Glycoprotein IIb/IIIa antagonists in the management of cardiovascular diseases. Am J Health Syst Pharm 55:2363-2386, 1998 47. The EPIC Investigation: Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Eng J Med 330:956-961, 1994 48. The EPILOG Investigators: Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 336:1689-1696, 1997 49. The CAPTURE Investigators: Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 349:1429-1435, 1997 50. The EPISTENT Investigators: Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 352:87-92, 1998 51. Mascelli MA, Lance ET, Damajaru L, et al: Pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade. Circulation 97:1680-1688, 1998 52. Tcheng JE, Ellis SG, George BS, et al: Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 90:1757-1764, 1994 53. The Abciximab in Ischemic Stroke Investigators: Abciximab in acute ischemic stroke. a randomized, double-blind, placebo-controlled, dose-escalation study. Stroke 31:601-609, 2000