Level 1: Likely reliable evidence and
Level 2: Mid-level evidence

In 2007, guidelines published by the American Heart Association/American Stroke Association (AHA/ASA) recommended recombinant tissue plasminogen activator (rt-PA, Alteplase) within three hours of symptom onset for selected adults with ischemic stroke (Stroke. 2007;38:1655-1711; available at stroke.ahajournals.org/cgi /reprint/38/5/1655. accessed August 12, 2009). The AHA/ASA has now expanded the time frame for rt-PA treatment to 4.5 hours after stroke onset, with some exceptions. Additional patient exclusions (rt-PA not indicated) during the 3- to 4.5-hour time frame are age older than 80 years, NIH stroke scale score >25, history of previous stroke or diabetes, or if taking oral anticoagulants (regardless of international normalized ratio). The updated recommendations can be found at stroke.ahajournals.org/cgi/reprint/STROKEAHA .109.192535v1, accessed August 12, 2009.

The new recommendation is based primarily on the third European Cooperative Acute Stroke Study (ECASS III) trial, which found that rt-PA given three to 4.5 hours after onset of nonsevere stroke reduced disability at 90 days (N Engl J Med. 2008;359:1317-1329; available at content.nejm.org/cgi /content/full/359/13/1317, accessed August 12, 2009). However, other randomized trials and observational studies have presented conflicting evidence. In the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) randomized trial, rt-PA given three to five hours after the onset of stroke increased rates of symptomatic and fatal intracranial hemorrhage with no apparent benefit in functional outcomes (JAMA. 1999;282:2019-2026; available at jama.ama-assn.org/cgi/content/full/282/21/2019, accessed August 12, 2009). The Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) observational study of 12,529 patients given rt-PA for ischemic stroke reported trends toward higher mortality and intracerebral hemorrhage rates associated with rt-PA treatment after three hours from stroke onset (Lancet. 2008;372:1303-1309).

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