European Cooperative Acute Stroke Study III - ECASS III

Description:

Current guidelines recommend thrombolysis for acute ischemic stroke if the presentation is within 3 hours of symptom onset, given a large body of evidence from clinical trials showing a significant benefit. Subsequent studies also indicated that this benefit was not noted if 3-6 hours had elapsed since symptom onset. Data from observational studies, however, indicated that the window for benefit may extend up to 4.5 hours. The ECASS III trial is the first randomized trial to evaluate whether there is a benefit with thrombolysis in patients with ischemic stroke presenting between 3 and 4.5 hours after symptom onset.

Hypothesis:

Thrombolytic therapy with alteplase will be safe and effective in patients with ischemic stroke presenting between 3 and 4.5 hours after symptom onset.

Study Design

Study Design:

Patients Enrolled: 821
Mean Follow Up: 3 months
Mean Patient Age: 65.3 years
Female: 40

Patient Populations:

  • Age 18-80 years
  • Acute ischemic stroke
  • Computed tomography (CT) or magnetic resonance imaging scan before randomization
  • Onset of symptoms between 3 and 4.5 hours before initiation of study drug
  • Stroke symptoms for at least 30 minutes without significant improvement prior to treatment

Exclusions:

  • Intracranial hemorrhage
  • Time of onset of stroke unknown
  • Symptoms rapidly improving or only minor prior to drug infusion
  • Severe stroke, involving more than one-third of the middle cerebral artery territory, with NIHSS score >25, or by appropriate imaging techniques
  • Seizure at the onset of stroke
  • Stroke or serious head trauma in the past 3 months
  • Combination of prior stroke and diabetes mellitus
  • Administration of heparin within the past 48 hours, with a partial thromboplastin time above the normal range
  • Platelet count <100,000/mm3
  • Systolic blood pressure >185 mm Hg or diastolic blood pressure >105 mm Hg, or aggressive blood pressure treatment (intravenous) necessary to reduce blood pressure to these limits
  • Blood glucose <50 or >400 mg%
  • Symptoms suggestive of subarachnoid hemorrhage, even with a normal CT scan
  • Oral anticoagulant treatment
  • Major surgery or severe trauma within the past 3 months
  • Other bleeding dyscrasias

Primary Endpoints:

Disability at day 90, as assessed by means of the modified Rankin scale, dichotomized as a favorable outcome (a score of 0 or 1) or an unfavorable outcome (a score of 2-6)

Secondary Endpoints:

Efficacy:
  • Global outcome measure that combined the outcomes at day 90 of a score of 0 or 1 on the modified Rankin scale, a score of 95 or higher on the Barthel Index, a score of 0 or 1 on the NIHSS, and a score of 1 on the Glasgow Outcome Scale
  • NIHSS score of 0-1, or more than an 8-point improvement in the score at 1 and 3 months
  • Modified Rankin score 0-2 at 1 and 3 months
  • Barthel Index ≥95 points at 1 and 3 months
Safety:
  • 90-day mortality
  • Any intracranial hemorrhage
  • Symptomatic ICH
  • Symptomatic edema
  • Serious adverse events

Drug/Procedures Used:

Eligible patients were randomly assigned to receive either 0.9 mg/kg of alteplase, administered intravenously (with an upper limit of 90 mg), or placebo. Of the total dose, 10% was administered as a bolus, and the remainder was given by continuous intravenous infusion over a period of 60 minutes.

Concomitant Medications:

Treatment with intravenous heparin, oral anticoagulants, aspirin, or volume expanders such as hetastarch or dextran during the first 24 hours after administration of the study drug had been completed was prohibited. However, the use of subcutaneous heparin (10,000 IU), or of equivalent doses of low-molecular-weight heparin, was permitted for prophylaxis against deep vein thrombosis.

Principal Findings:

A total of 821 patients were randomized, 418 to alteplase, and 403 to placebo; 10.0% of the patients were treated between 3 and 3.5 hours, 46.8% between 3.5 and 4 hours, and 39.2% between 4 and 4.5 hours, with the median being 3 hours and 59 minutes. Baseline characteristics were similar between the two groups, except for history of stroke, which was twice more frequent in the placebo arm, and the initial severity of stroke, which was higher in the placebo arm compared with alteplase (National Institutes of Health Stroke Scale [NIHSS] score 11.6 vs. 10.7, p = 0.03).

On intention-to-treat analysis, the primary endpoint (score of 0 or 1 on the modified Rankin scale) was significantly better in the alteplase arm compared with placebo at 90 days (52.4% vs. 45.2%, odds ratio [OR] 1.34, 95% confidence interval [CI] 1.02-1.76, p = 0.04). On multivariate analysis, alteplase was still associated with a favorable outcome (OR 1.42, 95% CI 1.02-1.98, p = 0.04). The secondary global outcome measure was significantly better with alteplase compared with placebo as well (OR 1.28, 95% CI 1.00-1.65, p < 0.05). Other functional outcomes such as modified Rankin scale score of 0-1 were better with alteplase at days 30 and 90, as well.

Overall mortality was similar between the two arms (7.7% vs. 8.4%), but intracranial hemorrhage (ICH) (including symptomatic ICH) was significantly higher with alteplase compared with placebo (27.0% vs. 17.6%, OR 1.73, 95% CI 1.24-2.42, p = 0.001). Other serious adverse effects were similar between the two groups.

Interpretation:

The results of this landmark trial indicate that alteplase is associated with better functional outcomes than placebo in patients with nonsevere ischemic strokes, when the presentation is between 3 and 4.5 hours after symptom onset, thus extending the window of benefit for patients with acute ischemic strokes. There is, however, a 73% higher risk of intracranial bleeding with alteplase, without any difference in overall mortality up to 3 months.

The outcome used by the investigators in this study is similar to that used by the landmark NINDS study (1995), where alteplase was associated with a significant improvement over placebo in patients presenting within 3 hours of symptom onset. Although the current study helps to extend the window for thrombolysis in these patients, it is important to note that there is a time-dependant decrement in the observed benefit: OR for a favorable global outcome 2.81 for an interval 0-90 minutes, 1.55 for 91-180 minutes, and 1.34-1.40 for 181-270 minutes. Hence, the earliest possible administration of thrombolytics in eligible patients is still critically important.

References:

Hacke W, Kaste M, Bluhmki E, et al., on behalf of the ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29.

Clinical Topics: Dyslipidemia, Noninvasive Imaging, Lipid Metabolism, Magnetic Resonance Imaging

Keywords: Outcome Assessment (Health Care), Thrombolytic Therapy, Stroke, Multivariate Analysis, Intracranial Hemorrhages, Intention to Treat Analysis, National Institute of Neurological Disorders and Stroke, Fibrinolytic Agents, Tissue Plasminogen Activator, Magnetic Resonance Imaging


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