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Treating stroke patients with intravenous (IV) alteplase (Activase, Genentech) beyond the accepted three-hour window is associated with a small increase in adverse events, but overall the benefits of any treatment over no treatment outweigh the risks, according to a substudy of the SITS-ISTR registry in the August edition of Lancet Neurology.

Niaz Ahmed, MD, of the Kreisklinikum-Siegen in Siegen, Germany, and colleagues evaluated a cohort of 2,376 patients from the SITS-ISTR (Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry) study that had been treated between three and 4.5 hours after stroke onset. 

In September 2008, guidelines recommended extending the time window from three hours out to 4.5 hours for IV alteplase treatment.

In the study, researchers found an increase from 5.7 to 19.7 percent of patients being treated within the extended time frame when comparing pre-September 2008 data to data from October 2008 to February 2010

The study identified 23,942 patients who presented with ischemic stroke and were treated across 650 centers between December 2002 and February 2010. During the substudy, the researchers analyzed patients who were treated both within three hours of symptoms onset and those treated within three hours to 4.5 hours after symptom onset.

For patients treated within three hours, the average time between symptom onset and alteplase treatment was 140 minutes compared to 205 minutes in patients treated within the extended window. The times between hospital admission and treatment were 65 minutes and 77 minutes, respectively.

The results showed that the rates of intracerebral hemorrhage were highest in patients treated within the three- to 4.5-hour window after symptom onset. Functional independence and mortality rates were also higher for the patients treated within the extended window.

“Although after adjustment, patients treated within three to 4.5 hours had higher symptomatic intracerebral hemorrhage and mortality rates and worse functional outcome than patients treated within three hours, the overall proportion of these outcomes was still low in the cohort treated within three to 4.5 hours and the statistical significance can probably be explained by the large sample size,” the authors wrote.

While the authors said that “the increases in the risk of symptomatic intracerebral hemorrhage and mortality in the later time window are minor and are outweighed by the benefit of the treatment, stroke onset-to-treatment time should be regarded as one of the most important contributing factors for favorable outcome, and the statistical significance is a warning for clinicians that treatment should not be delayed even though we now have an extended time window.”

In an accompaning editorial, Scott E. Kasner, MD, a professor of neurology at the Hospital of the University of Pennsylvania, and Steven R. Levine, MD, director of the Cerebrovascular Education Program at Mount Sinai School of Medicine in New York City, wrote: “Not only do these results confirm that trials can be extended into practice, but they also show that alteplase treatment up to 4.5 hours after stroke onset is increasingly accepted by clinicians worldwide.”

However, Kasner and Levine said real evidence outlining the effectiveness of alteplase treatment in stroke patients is lacking and more is needed to demonstrate the effectiveness of the treatment in the extended treatment window.

“At present, neither the European Medicines Agency nor the FDA have approved intravenous alteplase for acute ischemic stroke in the three- 4.5-hour time window,” the authors concluded. “Collaborative efforts—on political, educational and technological fronts—within stroke systems of care are essential for all who aim to improve the outcomes of patients with acute stroke.”