Study Confirms Benefit and Safety of Extending tPA Treatment Window

July 26, 2010—Nils Wahlgren, MD, et al have published findings from a study concluding that extension of the timeframe for alteplase treatment after acute stroke from 3 hours up to 4.5 hours is a safe option, and it has not resulted in delayed treatment of patients. The longer time window offers an opportunity to patients who cannot be treated earlier, but the benefits quickly lessen with time, and patients should be treated as early as possible. The study was published online ahead of print in The Lancet Neurology.

As detailed in The Lancet Neurology, previous research from ECASS III and SITS-ISTR has shown the benefit and safety of alteplase treatment in the 3- to 4.5-hour window after stroke. However, the SITS-ISTR study reported a possible increase in symptomatic intracerebral hemorrhage and death within 3 months in patients treated late (within 3–4.5 hours) compared with patients treated early (within 3 hours). Additionally, questions remained about whether the increased time window could result in a longer delay in treating patients and potentially affect outcomes because fast treatment still offers the best chance of recovery.

Dr. Wahlgren and colleagues conducted a follow-up safety analysis of data from SITS-ISTR to assess the implementation of the longer time window after the publication of the ECASS III and SITS-ISTR studies in September 2008. The investigators also evaluated the impact on admission-to-treatment time and sought to confirm or refute whether alteplase remains safe when given after 3 hours. A total of 23,942 patients were registered in SITS-ISTR between December 2002 and February 2010 and grouped according to whether they were registered before or after October 2008.
The investigators reported that the proportion of patients receiving alteplase treatment within 3 to 4.5 hours in the last quarter of 2009 was three times higher than in the first quarter of 2008 (282 of 1,293 [22%] vs 67 of 1,023 [7%]). The median admission-to-treatment time was 65 minutes for patients registered both before and after October 2008, suggesting that the extended time window had not resulted in delayed treatment of patients. After adjusting for confounding variables, patients treated within 3 to 4.5 hours had higher rates of symptomatic hemorrhage and death and a worse functional outcome at 3 months than patients treated within 3 hours.


The investigators commented, “Since October 2008, thrombolysis within 3 to 4.5 hours after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 hours. This has not been at the expense of increased delay from admission-to-treatment time. Increases in the risk of symptomatic intracerebral hemorrhage and mortality in the time window are minor and are outweighed by the benefit of treatment.”

 In conclusion, the investigators stated, “Alteplase remains safe when given with short treatment delays beyond 3 hours. Nevertheless, our results emphasize that patients should be treated as early as possible.”


In an accompanying editorial, Scott E. Kasner, MD, and Steven R. Levine, MD, point out that despite the ample evidence of the efficacy and effectiveness of alteplase, neither the European Medicines Agency or the US Food and Drug Administration have approved alteplase for use in the extended time window. They conclude by calling for regulatory approval to ensure that this treatment option is available to all patients.