American Heart Association 21st International Joint Conference on Stroke and Cerebral Circulation, San Antonio, Tex, January 25-27, 1996
Thrombolytic Treatment of Acute Stroke
One of the major highlights of the meeting was the well-publicized presentation of the National Institute of Neurological Disorders and Stroke (NINDS) TPA trial, which demonstrated that in appropriately selected stroke patients, treatment with TPA (0.9 mg/kg to 90 mg; 10% given as a bolus, 90% infused over 60 minutes) within 3 hours is associated with significantly less residual disability at 3 months than placebo. This study has already been published,1 but a number of other trials of thrombolytic therapy in acute stroke were also presented.
Dr Marc Hommell, of Grenoble, France, presented the results of the Multicenter Acute Stroke Trial-Europe (MAST-E). MAST-E compared streptokinase (1.5 million U IV over 1 hour) with placebo in acute stroke patients presenting within 6 hours of symptom onset. As originally designed, the trial was to include 600 patients, with efficacy assessed as a composite of death and disability (measured by the Rankin scale, a simplified overall assessment of function). However, the trial was halted prematurely at 310 patients because of an excess of in-hospital mortality in the streptokinase group (46.8% versus 38.3% with placebo). The investigators also noted moderate improvement in disability in stroke survivors treated with streptokinase.
Dr Geoffrey Donnan and Dr Stephen Davis, of Melbourne, Australia, presented the results of the Australian Streptokinase Study. In this study, involving 40 clinical centers in Australia, acute stroke patients were randomized to receive either streptokinase (1.5 million U IV over 60 minutes) or placebo within 4 hours of symptom onset. Both groups received 100 mg/d aspirin. The primary end point of the study was death or disability at 3 months; the study was originally designed to include 600 patients. This trial was also halted prematurely (n=340) because of excess mortality at 34 months in the streptokinase group (odds ratio, 2.2; 95% CI, 1.4 to 3.6). There was a nonsignificant trend toward a higher rate of combined 3-month death and disability in the streptokinase group. Patients treated within 3 hours of symptom onset had a nonsignificant trend toward better outcome with streptokinase. In the total population, patients treated within 3 hours did significantly better than patients treated >3 hours after symptom onset.
Dr Livia Candelise, of Milan, Italy, presented the results of the Multicenter Acute Stroke Trial-Italy (MAST-I). This study examined, in a factorial design, the benefits of aspirin (300 mg/d for 10 days) and streptokinase (1.5 million U over 60 minutes) in patients with acute stroke presenting within 6 hours of symptom onset. The study was stopped prematurely (at 622 patients) because of increased early mortality in the streptokinase group, especially in patients on aspirin who were treated 3 to 6 hours after symptom onset. There was, however, a significant decrease in six-month disability associated with thrombolytic use (40% with placebo, 26% with streptokinase).
Dr Markku Kaste, of Helsinki University Central Hospital in Finland, presented subgroup analysis from the European Cooperative Acute Stroke Study (ECASS). The overall trial, as previously described,2 showed that treatment within 3 hours in appropriately selected patients who received TPA was associated with less disability (Rankin scale and Barthel Index, an index of activity of daily living) at 90 days. Dr Kaste's analysis focused on identifying factors associated with favorable outcome in this study. Subgroups that showed particular benefit included patients treated early, patients with mild to moderate strokes, younger patients, and patients with a normal CT scan on admission. Dr Kaste again emphasized the importance of patient selection and of excluding patients with early infarct changes from treatment with thrombolytic agents.
Stroke Severity in Atrial Fibrillation
Dr Huey-Juan Lin and coworkers, of Boston (Mass) University School of Medicine, presented data from the Framingham study related to the outcome of strokes in patients with and without atrial fibrillation (AF). In the original Framingham cohort of 5070 subjects, 501 developed a stroke during subsequent follow-up; 103 of these were associated with AF. AF-associated strokes showed increased severity and a significantly higher 30-day case fatality rate (25% versus 14% for non-AF stroke). Functional status (as assessed by the Barthel index) was lower immediately after, at 3 months after, and at 6 months after AF-associated strokes but was not different at 12 months in stroke survivors. Dr Lin concluded that strokes associated with AF were nearly twice as likely to be fatal as non-AF strokes and that the resulting neurological deficits were more severe and disabling in AF-associated strokes.
Tirilizad in Acute Stroke
Two trials were presented on the use of the antioxidant tirilizad for acute stroke.
Dr Gary Peters, of the UpJohn Co in Kalamazoo, Mich, reported the final results of the TESS study, a placebo-controlled study that used an initial dose of 150 mg of tirilizad (given within 6 hours of stroke onset), followed by 6 mg·kg−1·d−1 for 3 days. The initial dose was given before CT evaluation, and subsequent doses were given after confirmation of the diagnosis of stroke. The trial was originally designed to include 1080 patients, but it was halted when an interim analysis of 450 patients suggested that the dose of tirilizad used in the study was too small to be effective. Approximately 50% of patients in both the placebo and active treatment groups had “favorable” recovery at 3 months (as judged by an expanded Barthel index and Glasgow Outcome Scale, a global assessment of function). Similarly, neurological function (according to the Unified Neurologic Stroke Scale) and 10-day and 3-month mortality rates were not different between groups. The TESS group is pursuing studies that use higher doses of tirilizad.
Dr Clarke Haley, of the University of Virginia, Charlottesville, presented the results of the North America-based RANTTAS (Randomized Trial of Tirilizad in Acute Stroke) study. Similar to TESS, in RANTTAS 150 mg tirilizad was administered as a bolus, followed by an intravenous dose of 6 mg·kg−1·d−1 in four divided doses for 3 days. The first dose was begun within 6 hours of symptom onset and could precede diagnostic CT confirmation. Outcome at 3 months was assessed with the Barthel index and the Glasgow Outcome Scale. Enrollment was stopped in December 1994, at 556 patients, when an interim analysis suggested that the likelihood of a favorable outcome with tirilizad was unacceptably low (P=.0006).
Piracetam in Acute Stroke
Professor Jacques DeReuck, of the University of Ghent, Belgium, reported the results of the Piracetam in Acute Stroke Study (PASS). Piracetam is an agent with antithrombotic, neuroprotective, and hemorheological properties. In PASS, 927 acute stroke patients were randomized to piracetam or placebo within 12 hours of symptom onset. Patients randomized to piracetam received a bolus dose of 12 g over 20 minutes, 12 g/d for 4 weeks, and 4.8 g/d for 8 weeks. The primary end point of the study, Orgogozo score (a measure of neurological outcome) at 4 weeks, showed no difference between groups, although there was a benefit from piracetam therapy as assessed by the 12-week Barthel Index scores, as well as a trend toward improvement in Orgogozo scores in patients who had the most severe strokes and who were treated within 6 hours. A new trial of piracetam is being designed that will focus on patients who had more severe strokes and who were treated within 6 hours.
- Copyright © 1996 by American Heart Association
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Ho¨xter G, Mahagne M, Hennerici M, for the ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA.. 1995;274:1017-1025.