Intravenous Recombinant Tissue-Type Plasminogen Activator in the Extended Time Window and the US Food and Drug Administration Confused About the Time
Intravenous Recombinant Tissue-Type Plasminogen Activator in the Extended Time Window and the US Food and Drug Administration Confused About the Time
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DOI：
10.1161/strokeaha.112.670554
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发表时间：
2012-09-01
期刊：
影响因子：
8.3
通讯作者：
Jovin, Tudor G.
中科院分区：
文献类型：
--
作者：
Wechsler, Lawrence R.;Jovin, Tudor G.
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 studies other than NINDS, the additional power provided by the larger number of patients in the 3-to 6-hour window now demonstrated a benefit of IV rt-PA treatment up to 4.5 hours. In 2002 the European Medicines Agency approved IV rt-PA for use in its member states after reviewing the available evidence. The approval was conditional on performing a confirmatory study in Europe, but a placebo-controlled trial in the 0-to 3-hour window was not thought possible given the prevalent opinion in the community regarding the efficacy of IV rt-PA in this time window. Therefore, ECASS III, a placebo-controlled study investigating the benefit of IV rt-PA when administered within the 3-to 4-hour time window, was initiated and subsequently expanded to include patients up to 4.5 hours after stroke onset. At the same time, an observational registry of all patients treated with IV rt-PA under approved indication was commissioned. In 2008 the results of ECASS III including 821 patients demonstrated significant benefit of IV rt-PA compared with placebo (OR, 1.34; 95% CI, 1.02–1.76; P 0.04). 10 A large observational study of patients treated with IV rt-PA in 650 centers outside the United States found similar outcomes in patients treated 3 to 4.5 hours after stroke compared with those treated within 3 hours; however, patients treated in the longer window had lower stroke severity (median National Institutes of Health Stroke Scale 12 versus 10, P 0.001), slightly younger age (68 versus 67, P 0.007), and were more likely to have small vessel disease (10% versus 13%, P 0.001). 11, 12 After adjusting for all imbalances in baseline variables, outcomes were better in the 0-to 3-hour group but differences were small. In ECASS III, a significant imbalance in baseline National Institutes of Health Stroke Scale favored …
