Abciximab in acute ischemic stroke. A randomized, double-blind, placebo-controlled, dose-escalation study. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Effects of ticlopidine on the neurologic outcome and the hemorheologic pattern in the postacute phase of ischemic stroke: a pilot study. Aspirin in the prevention of progressing stroke: a randomized controlled study. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial--Italy (MAST-I) Group. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial.
Abciximab is a potent parenterally administered platelet glycoprotein IIb/IIIa antagonist. Because this agent has been shown to improve outcomes in coronary artery disease, there is interest to evaluate whether it could improve cerebral perfusion and outcomes after ischemic stroke. This study was designed to evaluate the safety of abciximab in acute ischemic stroke and to obtain pilot efficacy data.
                We conducted a randomized, double-blind, placebo-controlled, dose-escalation trial. Seventy-four eligible and consenting patients presenting within 24 hours after ischemic stroke onset at 38 study sites were randomly allocated to receive either an escalating dose of abciximab (54 patients) or placebo (20 patients) in a ratio of 3:1. We studied 4 escalating doses of abciximab. Patients underwent a scheduled follow-up head CT scan 24 to 36 hours after the completion of study agent administration to monitor for bleeding complications and were evaluated through 3 months.
                There were no cases of major intracranial hemorrhage. Asymptomatic parenchymal hemorrhages were detected on post-study agent CT in 4 of 54 abciximab patients (7%) and in 1 of 20 placebo patients (5%). Six additional abciximab patients had asymptomatic hemorrhagic lesions detected by unscheduled brain imaging during their follow-up period. Nine of 11 patients with asymptomatic hemorrhage had a baseline National Institutes of Health Stroke Scale score >14. At 3 months, there was a trend toward a higher rate of minimal residual disability (Barthel Index > or =95 or modified Rankin scale < or =1) among abciximab patients compared with those who received placebo.
                Abciximab appears to be safe when administered up to 24 hours after stroke onset, and it might improve functional outcome. Aspirin is effective in the treatment of acute myocardial infarction and in the long-term prevention of serious vascular events in survivors of stroke and myocardial infarction. There is, however, no reliable evidence on the effectiveness of early aspirin use in acute ischaemic stroke.
                The Chinese Acute Stroke Trial (CAST) was a large randomised, placebo-controlled trial of the effects in hospital of aspirin treatment (160 mg/day) started within 48 h of the onset of suspected acute ischaemic stroke and continued in hospital for up to 4 weeks. The primary endpoints were death from any cause during the 4-week treatment period and death or dependence at discharge, and the analyses were by intention to treat. 21,106 patients with acute ischaemic stroke were enrolled in 413 Chinese hospitals at a mean of 25 h after the onset of symptoms (10,554 aspirin, 10,552 placebo). 87% had a CT scan before randomisation. It was prospectively planned that the results would be analysed in parallel with those of the concurrent. International Stroke Trial (IST) of 20,000 patients with acute stroke from other countries.
                There was a significant 14% (SD 7) proportional reduction in mortality during the scheduled treatment period (343 [3.3%] deaths among aspirin-allocated patients vs 398 [3.9%] deaths among placebo-allocated patients; 2p = 0.04). There were significantly fewer recurrent ischaemic strokes in the aspirin-allocated than in the placebo-allocated group (167 [1.6%] vs 215 [2.1%]; 2p = 0.01) but slightly more haemorrhagic strokes (115 [1.1%] vs 93 [0.9%]; 2p > 0.1). For the combined in-hospital endpoint of death or non-fatal stroke at 4 weeks, there was a 12% (6) proportional risk reduction with aspirin (545 [5.3%] vs 614 [5.9%]; 2p = 0.03), an absolute difference of 6.8 (3.2) fewer cases per 1000. At discharge, 3153 (30.5%) aspirin-allocated patients and 3266 (31.6%) placebo-allocated patients were dead or dependent, corresponding to 11.4 (6.4) fewer per 1000 in favour of aspirin (2p = 0.08).
                There are two major trials of aspirin in acute ischaemic stroke. Taken together, CAST and the similarly large IST show reliably that aspirin started early in hospital produces a small but definite net benefit, with about 9 (SD 3) fewer deaths or non-fatal strokes per 1000 in the first few weeks (2p = 0.001), and with 13 (5) fewer dead or dependent per 1000 after some weeks or months of follow-up (2p < 0.01). A previous randomized, placebo-controlled, double-blind study suggested that abciximab may be safe and effective in treatment of acute ischemic stroke. The current phase 3 study was planned to test the relative efficacy and safety of abciximab in patients with acute ischemic stroke with planned treatment within 5 hours since symptoms onset.
                An international, randomized, placebo-controlled, double-blind phase 3 trial tested intravenous administration of abciximab in 2 study cohorts using stratification variables of time since onset and stroke severity. The planned enrollment was 1800 patients. The primary cohort enrolled those patients who could be treated within 5 hours of onset of stroke. A companion cohort enrolled patients that were treated 5 to 6 hours after stroke as well as a smaller cohort of patients who could be treated within 3 hours of stroke present on awakening. The primary efficacy measure was the dichotomous modified Rankin Scale score at 3 months as adjusted to the baseline severity of stroke among subjects in the primary cohort. The primary safety outcome was the rate of symptomatic or fatal intracranial hemorrhage that occurred within 5 days of stroke.
                The trial was terminated prematurely after 808 patients in all cohorts were enrolled by recommendation of an independent safety and efficacy monitoring board due to an unfavorable benefit-risk profile. At 3 months, approximately 33% of patients assigned placebo (72/218) and 32% of patients assigned abciximab (71/221; P=0.944) in the primary cohort were judged to have a favorable response to treatment. The distributions of outcomes on the modified Rankin Scale were similar between the treated and control groups. Within 5 days of enrollment, approximately 5.5% of abciximab-treated and 0.5% of placebo-treated patients in the primary cohort had symptomatic or fatal intracranial hemorrhage (P=0.002). The trial also did not demonstrate an improvement in outcomes with abciximab among patients in the companion and wake-up cohorts. Although the number of patients was small, an increased rate of hemorrhage was noted within 5 days among patients in the wake-up population who received abciximab (13.6% versus 5% for placebo).
                This trial did not demonstrate either safety or efficacy of intravenous administration of abciximab for the treatment of patients with acute ischemic stroke regardless of end point or population studied. There was an increased rate of symptomatic or fatal intracranial hemorrhage in the primary and wake-up cohorts. This double-blind pilot study observed the effects of a twenty-one day oral ticlopidine treatment (250 mg/twice daily) on the neurologic outcome and the hemorheologic pattern of 15 patients and 15 placebo-treated controls. Patients and controls (age range sixty-six to eighty-six years) were included in the study within twelve hours of the onset of ischemic stroke, confirmed clinically and by computerized tomography. Scores on Hachinski's Scale and the following hemorheologic parameters were monitored weekly for twenty-one days: fibrinogen levels, the whole blood, unfractionated white and red blood cell filterability rates (through 5-micron-pore-diameter filters using a constant-flow positive-pressure system), and the leukocyte count and activation (by microscopic observation). The results showed treatment with ticlopidine improved the neurologic outcome (Hachinski's Score +36%, p less than 0.03) slightly but significantly (p less than 0.001) increased the average values of the whole blood (+19%) and red cell (+17%) filterability rates and decreased fibrinogen levels (-17%). In acute stroke, progression has a severe impact on patient outcome and no effective treatment is known. The main objective was to evaluate the efficacy of aspirin for prevention of stroke progression thereby improving outcome.
                The trial was randomized, double-blind and placebo-controlled.
                The patients were treated in stroke units of four hospitals in Sweden.
                Patients with ischaemic stroke but not complete paresis were included. No antiplatelet drugs were allowed within the last 72 h before onset. Delay until first trial dosage was maximized to 48 h. The trial was designed to detect a 20% reduction of the rate of stroke progression, which was estimated to take place in 20% of cases. Totally, 441 patients (220 aspirin, 221 placebo) completed the trial. Baseline comparisons between the groups showed no differences.
                Aspirin (325 mg) or placebo was given once daily for five consecutive days.
                Neurological assessments were carried out three times daily during the treatment period to detect progression of at least two points in the Scandinavian Stroke Supervision Scale. Patient outcome was followed up at discharge and at 3 months.
                Aspirin treatment did not significantly reduce the frequency of stroke progression. Amongst aspirin-treated patients, stroke progression occurred in 15.9% as compared with 16.7% in the placebo group, which is less frequent than expected. The relative risk was 0.95 (95% CI 0.62-1.45) in the treatment group. As regards patient outcome at discharge and after 3 months, aspirin treatment did not show any difference.
                No positive effect of aspirin, of the expected size, could be shown on the frequency of stroke progression or patient outcome. In ischaemic stroke, thrombolytic drugs speed the recanalisation of intracerebral arteries. The effects of aspirin are not known. A trial was conducted to determine whether, separately or together, streptokinase and aspirin have clinical benefits in acute ischaemic stroke similar to those in acute myocardial infarction. 622 patients with acute ischaemic stroke within 6 hours of symptom onset were randomised with a 2 x 2 factorial design to (i) a 1-hour intravenous infusion of 1.5 MU streptokinase, (ii) 300 mg/day buffered aspirin for 10 days, (iii) both active treatments, or (iv) neither. Early results raised a question whether the trial should be continued. Streptokinase (alone or with aspirin) was associated with an excess of 10-day case fatality (odds ratio 2.7; 95% confidence interval 1.7-4.3; 2p < 0.00001). Of the four groups randomised, only patients allocated to streptokinase plus aspirin had a significantly higher risk of early death than those given neither streptokinase nor aspirin (odds ratio 3.5; 95% CI 1.9-6.5; 2p < 0.00001). Streptokinase (alone or with aspirin) and aspirin (alone or with streptokinase) reduced, albeit not significantly, the incidence of combined six-month case fatality and severe disability: odds ratio for streptokinase 0.9 (95% CI 0.7-1.3) and odds ratio for aspirin 0.9 (95% CI 0.6-1.3). The risk of early death with thrombolytic treatments should be weighed against the potential benefit of a marginal reduction of severe disability after the first six months. Because of its success in treatment of acute cardiac ischemia, there is interest in the use of abciximab for treating patients with acute ischemic stroke. A previous dose-escalation study determined that abciximab could be given safely in a regimen of 0.25 mg/kg intravenous bolus followed by a 12-hour infusion at 0.125 microg/kg per minute (maximum 10 microg/min). This study was performed to obtain more information about the safety and potential efficacy of abciximab in patients with stroke.
                An international randomized, double-blind, placebo-controlled phase 2 trial enrolled 400 patients within 6 hours of onset of ischemic stroke. The primary safety outcome was the rate of symptomatic hemorrhage that occurred during the first 5 days after stroke. The primary efficacy measure was the distribution of outcomes at 3 months after stroke using the modified Rankin Scale (mRS) based on an ordinal regression model of outcomes, adjusting for baseline severity of stroke, age, and interval from stroke.
                Symptomatic intracranial hemorrhage within 5 days was diagnosed in 7 of 195 (3.6%) patients treated with abciximab and 2 of 199 (1%) patients given placebo (odds ratio [OR], 3.7; P=0.09; 95% confidence interval [CI], 0.7 to 25.9). Asymptomatic hemorrhagic transformation was detected by brain imaging in 24 patients administered abciximab and 33 patients receiving placebo (OR, 0.74; P=0.25; 95% CI, 0.4 to 1.3). Treatment with abciximab showed a nonsignificant shift in favorable outcomes as measured by mRS scores at 3 months (OR, 1.20; P=0.33; 95% CI, 0.84 to 1.70).
                Intravenously administered abciximab can be given to patients with a reasonable degree of safety. The trial also suggests that abciximab could improve outcomes at 3 months after stroke. A larger randomized, double-blind, placebo-controlled trial is necessary to test the efficacy of abciximab.
Antiplatelet therapy with aspirin 160 mg to 300 mg daily, given orally (or by nasogastric tube or per rectum in patients who cannot swallow), and started within 48 hours of onset of presumed ischaemic stroke reduces the risk of early recurrent ischaemic stroke without a major risk of early haemorrhagic complications and improves long-term outcome.