Intravenous recombinant tissue-type plasminogen activator in the extended time window and the US Food and Drug Administration: confused about the time.

Since the earliest trials of intravenous (IV) recombinant tissue-type plasminogen activator (rt-PA) for treatment of acute stroke, the time window for clinical efficacy has been controversial. Preclinical studies suggested an increased hemorrhage rate when thrombolytics were administered at later time intervals after arterial occlusion. The first US pilot study of IV rt-PA demonstrated acceptable safety using a 90-minute time window at doses up to 1.08 mg/kg.1 In a subsequent study extending treatment to 91 to 180 minutes, more hemorrhages occurred with less apparent efficacy but outcomes were considered possibly better than the natural history.2 This formula was carried over to the pivotal National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial stratifying patients to treatment within 90 minutes and 91 to 180 minutes after stroke.3 A subsequent analysis showed the OR for favorable outcome at 3 months after rt-PA decreased with time from stroke onset approaching unity at 180 minutes.4 Other studies of IV rt-PA including European Cooperative Acute Stroke Study (ECASS),5 ECASS II,6 and Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS)7 enrolled patients up to 6 hours from stroke onset but failed to confirm the beneficial effect of IV rt-PA. Notably, none of these studies demonstrated a relationship between risk of symptomatic hemorrhage and time to treatment, although few patients within 3 hours of stroke onset were included.8 Based on the results of the NINDS rt-PA trial, the US Food and Drug Administration (FDA) approved IV rt-PA for treatment of acute stroke in 1996 but limited the approval to the study time window, 3 hours. In 2004 a pooled analysis of 4 randomized IV rt-PA trials, NINDS, ECASS, ECASS II, and ATLANTIS, was published.9 Although few patients were added to the 0- to 3-hour group from …

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