ECASS 3: Thrombolysis Beneficial Up to 4.5 Hours After Acute Ischemic Stroke

Susan Jeffrey

September 24, 2008

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September 24, 2008 — Results of a randomized trial suggest that treatment with tissue plasminogen activator (tPA) given 3 to 4.5 hours after symptom onset can still provide "modest but significant" improvement in clinical outcomes after an acute ischemic stroke vs placebo.

The trial, the third European Cooperative Acute Stroke Study (ECASS 3), showed that although symptomatic intracerebral hemorrhage was higher in treated patients, the rate was not higher than that reported previously among patients treated within the currently approved 3-hour window and was not associated with increased mortality.

However, the ECASS investigators, with lead author Werner Hacke, MD, from the University of Heidelberg, in Germany, caution that treatment as early as possible after symptom onset is still the goal.

"Having more time does not mean we should be allowed to take more time," the authors emphasize.

The results appear in the September 25 issue of the New England Journal of Medicine and will be presented at the World Stroke Congress in Vienna the same day. The study was supported by Boehringer Ingelheim.

Thinking Outside the Window

Intravenous tPA is the only approved treatment for acute ischemic stroke, but the approval is limited to use within 3 hours of symptom onset. Its efficacy and safety when given beyond that time period is not established, although there has been some indication from a pooled analysis of the randomized trials that there may be benefit beyond 3 hours, up to 4.5 hours, the authors note.

Another report indicating some evidence of benefit beyond 3 hours was published online September 15 in the Lancet (Wahlgren N et al. Lancet 2008). Results from the Safe Implementation of Treatments in Stroke — International Stroke Thrombolysis Registry (SITS-ISTR), an observational audit of patients treated with intravenous tPA for acute ischemic stroke, showed no significant difference in outcomes between patients treated between 3 and 4.5 hours post–symptom onset and those treated prior to the recommended threshold of 3 hours.

"Today, only a minority of stroke patients can be treated, mainly because of the restriction of the time window, and an increase of that window by 50% would make it possible to treat more patients," first author Nils Wahlgren, MD, from Karolinska University Hospital, in Stockholm, Sweden, said in an interview. However, a change in practice would await evidence of benefit from a randomized trial.

ECASS 3 was a randomized trial comparing tPA treatment with placebo in 821 stroke patients presenting 3 to 4.5 hours after symptom onset. After those with evidence of brain hemorrhage or major infarction on CT scan were excluded, patients were randomized to receive treatment with intravenous tPA in the approved regimen of 0.9 mg/kg body weight (n = 418) or placebo (n = 403).

In this trial, the median time for the administration of tPA was 3 hours and 59 minutes. About 10% were treated between 3 and 3.5 hours, 50% between 3.5 and 4 hours, and 40% between 4.0 and 4.5 hours.

The primary end point was disability at 90 days, dichotomized as a favorable outcome (modified Rankin Scale [mRS] 0 or 1) or unfavorable outcome (mRS 2 to 6).

The authors report that significantly more patients treated with tPA had a favorable outcome by this measure than those who received placebo.

ECASS 3 Primary End Point: Favorable Outcome at 90 Days by Treatment Group

End Point tPA Placebo Odds Ratio (95% CI) P
Favorable outcome (mRS 0 or 1) at 90 days (%) 52.4 45.2 1.34 (1.02 – 1.76) .04

A secondary end point, a global analysis combining 4 neurologic and disability scores, also showed an improvement with treatment vs placebo (odds ratio, 1.28 [95% CI, 1.00 – 1.65]; P < .05).

In terms of safety, the incidence of intracerebral hemorrhage (ICH) and symptomatic ICH was significantly higher with tPA than placebo, the authors note, although this difference did not translate into an increase in mortality.

ECASS 3: Intracerebral Hemorrhage (ICH) and Mortality by Treatment Group

End Point tPA Placebo P
Any ICH 27.0 17.6 .001
Symptomatic ICH 2.4 0.2 .008
Mortality 7.7 8.4 .68

The authors point out that in ECASS 3, they modified the ECASS definition of symptomatic ICH by specifying that the hemorrhage had to have been identified as the predominant cause of the neurologic deterioration. Using that definition, the rate was higher with treatment than placebo but was still low overall.

When they used the definitions used in other trials, they add, "the rate of symptomatic intracerebral hemorrhage in our trial was no higher than that reported in previous randomized trials or in [the Safe Implementation of Thrombolysis in Stroke — Monitoring Study] SITS-MOST, despite the extended time window in our study."

There was no significant difference in the rate of other adverse events, they note.

A Long, Difficult Path

In an editorial accompanying the paper, Patrick Lyden, MD, from the University of California, San Diego, points out that the results of ECASS 3, like the National Institute of Neurological Disorders and Stroke (NINDS) trial that established the efficacy of tPA in stroke treatment, was robust across multiple end points, and showed efficacy for treatment despite an increased rate of hemorrhage. Based on this, he writes, "one cannot help wondering why thrombolytic therapy has traveled such a long, difficult path to wider clinical use."

The inclusion and exclusion criteria for ECASS 3 were broad, and in general, patients who present with an acute stroke will qualify for treatment, he writes. When collected properly, the evidence consistently shows that one-third of patients with stroke come to an emergency department within the appropriate time window and satisfy the criteria for thrombolytic therapy, Dr. Lyden writes.

"The frequently quoted statistic that only 4% of all patients with stroke receive [recombinant tissue plasminogen activator] rt-PA must be viewed as an important indictment of our healthcare system and of the field of neurology in particular," he asserts. "The patients are coming in, but we are not."

Policies and procedures should be instituted to ensure that patients are promptly identified and treated, quality outcome data must be used to select and designate treatment centers of excellence for patients with acute stroke, and patients should be diverted to these centers, Dr. Lyden concludes. "The public expects no less, and given the past decade of distortion of the NINDS study findings and delay in implementing thrombolytic therapy for acute stroke, we have not a minute to lose."

ECASS 3 was supported by Boehringer Ingelheim. Dr. Hacke reports receiving consulting, advisory board, and lecture fees from Paion, Forest Laboratories, Lundbeck, and Boehringer Ingelheim and grant support from Lundbeck. Disclosures for other ECASS investigators appear in the paper. Dr. Lyden reports no conflict of interest relevant to his editorial.

N Engl J Med. 2008;359:1317-1329, 1393-1395.


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