Acute Ischemic Stroke

Acute Ischemic Stroke

Acute Ischemic StrokeAcute ischemic stroke (AIS) is an infarction of brain tissue caused by cerebral ischemic artery stenosis or occlusion of insufficient cerebral blood supply, accompanied by injury of neuronal astrocyte oligodendrocytes. It most commonly occurs when a blood vessel is obstructed leading to irreversible brain injuries and subsequent focal neurologic deficits. In the USA, AIS is the fourth leading cause of death and the leading cause of adult disability. There are approximately 795,000 new or recurrent strokes each year, and an estimated $73.7 billion is required in 2010 alone. Of all strokes, AIS accounts for about 85 %.

Drug treatment of AIS involves intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator [rtPA]). Intravenous alteplase promotes thrombolysis by hydrolyzing plasminogen to form the proteolytic enzyme plasmin. However, plasmin targets the blood clot with limited systemic thrombolytic effects, and alteplase must be administered within a short time window to appropriate patients to optimize its therapeutic efficacy. International guidelines recommend alteplase as a first-line treatment for eligible patients when administered within 3 hours after the onset of stroke. We design to test the hypothesis that the efficacy of alteplase administered in patients with acute ischemic stroke can be safely extended to a time window of 3 to 4.5 hours after the onset of stroke symptoms.

Case Study

Randomization is a remarkable step in most clinical trials. First, eligible patients were randomly assigned, in a 1:1 ratio, to receive 0.9 mg of alteplase per kilogram, administered intravenously (with an upper limit of 90 mg), or placebo. We used the interactive voice-randomization system, with randomization at centers performed to ensure the balance of distribution. Additionally, the examiner was unaware of the patients’ treatment assignment when assessing patients.

Another challenge is statistical analysis. For the primary end point, we used the chi-square test of proportions (with a two-sided alpha level of 5%) to calculate between-group differences. Ninety-five percent confidence intervals were calculated for odds ratios and for relative risk. In addition, we undertook a post hoc adjusted analysis (logistic regression) of the primary end point in the intention-to-treat population. This analysis was performed by including all baseline variables in the model and retaining those that were significant at P<0.10. For the secondary end point — the probability of a favorable outcome with alteplase as compared with placebo — a global odds-ratio test based on a linear logistic regression model (a method that uses generalized estimation equations to perform a Wald-type test) was used. Besides, we applied the same statistical tests for the per-protocol population. The calculation of the sample size was based on the analysis of pooled data from the cohorts that received thrombolysis or placebo between 3 and 4.5 hours after the onset of symptoms. On the basis of these data, we calculated that 400 patients per group were required in order to have 90% power to detect an odds ratio of 1.4 for the primary end point.

Using this randomization method and statistical strategy, we assigned eligible patients randomly and analyzed results in a trial of alteplase treatment in acute ischemic stroke.


A multicenter, randomized, double-blind, placebo-controlled, phase 3, parallel group trial.


From multiple centers, there are 821 patients who may have acute ischemic stroke (Figure 1). All recruited patients had performance as follows:

  • Acute ischemic stroke.
  • They are between 18-80 years old.
  • They develop stroke symptoms 3 to 4.5 hours before initiation of study-drug administration.
  • All of these patients exhibit motor hyperactivity, physical aggression, or verbal aggression.
  • They present stroke symptoms for at least 30 minutes with no significant improvement before treatment.
  • They must receive the cerebral computed tomographic (CT) scans and be diagnosed without an intracranial hemorrhage or major ischemic infarction.

Participant flow

Figure 1. Participant flow

Length of Enrollment Period:

51 months.


Participants (n=821) were randomized to receive either alteplase (n=418) or placebo (n=403) interventions. They received 0.9 mg of alteplase per kilogram, administered intravenously (with an upper limit of 90 mg), or placebo. Grouped according to 0.5-hour intervals, 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. (The values do not add up to 100% because data on the exact time of treatment initiation were not available for 12 patients in the alteplase group and 15 patients in the placebo group; in addition, treatment was initiated after 4.5 hours in 1 patient in the alteplase group and 5 patients in the placebo group.)

Main Outcomes:

  • National Institutes of Health Stroke Scale (NIHSS)
  • CT/MRI
  • Modified Rankin Scale (mRS)
  • Barthel Index
  • Glasgow Outcome Scale (GOS)


The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04).  The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events (table 1).

Table 1. Odds Ratios for Primary End Point and Secondary End Point, Including Components, in the Intention-to-Treat and Per-Protocol Populations at 90 Days

Odds Ratios for Primary End Point and Secondary End Point

CI = confidence interval; NIHSS= National Institutes of Health Stroke Scale; mRS= modified Rankin scale; GOS= Glasgow Outcome Scale

* The primary efficacy end point was disability at day 90 (3-month visit), 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 to 6). The secondary efficacy end point was a 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. Further functional end points were based on predefined cutoff points for the NIHSS score (a score of 0 or 1, or more than an 8-point improvement in the score), the score on the modified Rankin scale (dichotomized as 0 to 2 or 3 to 6), and the Barthel Index ( 95 points), assessed on day 90 and also on day 30.

† P value was obtained by the Pearson chi-square test of proportions.

‡ This analysis was adjusted for NIHSS score at presentation and the time to start of treatment.

§ P value was obtained by stepwise logistic regression.

‖Scores on the modified Rankin scale range from 0 (no symptoms at all) to 6 (death).

** The Barthel Index assesses the ability to perform activities of daily living on a scale that ranges from 0 (complete dependence on help with activities of daily living) to 100 (independence).

†† Scores on the NIHSS range from 0 to 42, with higher values reflecting more severe neurologic impairment (<5, mild impairment; 25, very severe impairment).

‡‡ The Glasgow Outcome Scale is a 5-point scale on which 1 indicates independence, 3 severe disability, and 5 death.

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1. Bansal, S., Sangha, K. S., & Khatri, P. (2013) ‘Drug treatment of acute ischemic stroke’ American Journal of Cardiovascular Drugs, 13(1), 57-69.
2. Hacke, W., Kaste, M., Bluhmki, E., Hacke, W., Kaste, M., & Bluhmki, E. (2008) ‘Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke’ Journal of Vascular Surgery, 48(6), 1634-1635.

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