The much-publicized findings from the European Cooperative Acute Stroke Study (ECASS) III, which support administering thrombolytic therapy up to 4.5 hours from stroke symptom onset, could have significant implications for practitioners involved in helping stroke patients regain their mobility and functional independence.

In the Sept. 25 issue of the New England Journal of Medicine, the ECASS III group reported that patients randomized to receive the thrombolytic drug alteplase between three and 4.5 hours of stroke onset had significantly better 90-day outcomes than those treated with placebo.

The study’s primary outcome measure was the modified Rankin scale (mRs), in which a score of 0 indicates no disability and a score of 6 signifies death. A favorable outcome was defined as an mRs score of 0 or 1, including patients with no symptoms and those whose symptoms did not prevent them from carrying out all usual duties and activities as they had prior to stroke onset. Of the 418 patients who received alteplase (an average of three hours 59 minutes after onset), 52.4% had a favorable outcome at 90 days, compared with 45.2% of those who received placebo.

Rates of intracranial hemorrhage were significantly higher in the alteplase group than the placebo group, but were similar to rates seen within the three-hour window in previous studies.

The third time was the charm for the ECASS researchers, who had twice previously attempted to document a therapeutic benefit of administering alteplase beyond the three-hour window approved by the Food and Drug Administration in 1996. The two earlier prospective trials failed to support expanding that therapeutic window to six hours, though a 2006 meta-analysis suggested that a cut-off between three and six hours might yield better results.

Although the outcomes in the ECASS III treatment group did not reach the levels seen in patients treated within three hours, the findings still suggest that expanding the window for delivery of alteplase (or another type of tissue plasminogen activator) could potentially make rehab specialists’ work easier in a greater number of cases. Although impairments in stroke patients can involve speech, vision, or other sensory areas, motor function is thought to be a key component of a favorable outcome.

“Patients treated with tPA typically have motor deficits among the deficits they have. The primary deficits that will handicap a patient with stroke are either related to motor or speech,” said Warren L. Felton, III, MD, a professor of neurology and medical director of the stroke program at Virgina Commonwealth University Medical Cen­ter in Richmond. “The (ECASS III) outcomes were seen at 90 days, so that would have been well beyond the acute phase of stroke and clearly into the period when those patients would have been undergoing rehabilitation.”

Often the best way to maximize rehab outcomes is to minimize the initial deficits, said Joel Stein, MD, chair of the department of rehabilitation medicine at Columbia University and chief of the division of rehabilitation medicine at Weill-Cornell Me­dical Center. As an example, Stein cited the November 2006 EXCITE study, in which the magnitude of improvement with constraint-induced movement therapy was similar regardless of baseline function level.

“What’s very striking is that the people who were more severely impaired to begin with never caught up to those who were less severe to begin with,” he said. “We as clinicians can help, but the initial deficit is terribly important. If that deficit is less severe, then we’re starting from a better place.”

Theoretically, expanding the treatment window to 4.5 hours would significantly increase patient access to thrombolytic therapy, which experts agree is sorely needed. Published reports have estimated that just 2% to 4% of all stroke patients currently receive this type of treatment, often because they do not arrive at the hospital in time.

However, the ECASS group and others caution that just because a therapeutic benefit might exist at 4.5 hours does not mean clinicians should wait that long to administer thrombolytic therapy if it is possible to do so sooner. In fact, research suggests that as the time from symptom onset increases, so does the risk of disability.