Results of intravenous thrombolysis within 4.5 to 6 hours and updated results within 3 to 4.5 hours of onset of acute ischemic stroke recorded in the safe implementation of treatment in Stroke International Stroke Thrombolysis Register (SITS-ISTR)An Observational Study

Ahmed, N., Kellert, L., Lees, K.R., Mikulik, R., Tatlisumak, T. and Toni, D. (2013) Results of intravenous thrombolysis within 4.5 to 6 hours and updated results within 3 to 4.5 hours of onset of acute ischemic stroke recorded in the safe implementation of treatment in Stroke International Stroke Thrombolysis Register (SITS-ISTR)An Observational Study. JAMA Neurology, 70(7), pp. 837-844. (doi: 10.1001/jamaneurol.2013.406)

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Abstract

Importance:  Pooled analysis of randomized controlled trials of intravenous thrombolysis shows no statistically significant benefit beyond 4.5 hours, with the possible advantage perhaps offset by risk. Objective:  To compare the outcomes of patients who were treated within 4.5 to 6 hours or within 3 to 4.5 hours of the onset of an ischemic stroke with the outcomes of patients who were treated within 3 hours in the SITS-ISTR. Design: An observational study based on SITS-ISTR data during the period from 2002 to 2011. Setting: Acute and emergency care. Participants: Of 29 618 patients with acute ischemic stroke, 283 (1.0%) were treated within 4.5 to 6 hours of onset, 4056 (13.7%) were within 3 to 4.5 hours of onset, and 25 279 (85.4%) were treated within 3 hours of onset, in compliance with other European Union approval criteria. Exposure: Intravenous thrombolysis with alteplase. Main Outcomes and Measures: Functional independence (modified Rankin Scale score of 0-2) and mortality at 3 months and symptomatic intracerebral hemorrhage (SICH). P values are based on comparisons between patients treated within 4.5 to 6 hours or within 3 to 4.5 hours of onset against patients treated within 3 hours of onset. Results:  Results are presented as within 4.5 to 6 hour vs within 3 to 4.5 hours vs within 3 hours. Median time from stroke onset to treatment was 295 vs 210 minutes vs 138 minutes (P < .01), median age was 65 vs 67 vs 68 years (P < .01), and median baseline National Institutes of Health Stroke Scale score was 9 vs 9 vs 12 (P <.01). Rate of functional independence was 61.3% (P = .40) vs 62.7% (P <.01) vs 58.4%; mortality rate was 11.8% (P = .99) vs 11.1% (P = .21) vs 11.8%; and rate of SICH was 2.6% (P = .17) vs 1.8% (P = .27) vs 1.5%. Multivariate analysis detected no significant difference in SICH (P> .05), mortality (P> .05), or independence (P> .05). Time from stroke onset to treatment as a continuous variable was significantly associated with higher rates of SICH and poor 3-month outcome after adjustment for age and National Institutes of Health Stroke Scale score. Conclusions and Relevance:  The treatment remains safe and effective for patients treated within 3 to 4.5 hours compared with patients treated within 3 hours. Our selected group of patients treated within 4.5 to 6 hours of stroke onset did not have worse outcomes than patients treated within 3 hours. An inevitable limitation of our observational study is the possible nonequivalence of the cohorts, particularly the 4.5- to 6-hour cohort relative to the other 2 cohorts. Intravenous alteplase, a recombinant tissue plasminogen activator, is the only pharmacological therapy that is approved for treatment within 3 hours of ischemic stroke onset. Recently, the treatment approval with alteplase has been extended in many countries to up to 4.5 hours after stroke onset. Most guidelines1- 2 already recommended treatment up to 4.5 hours after stroke onset after the publication of the European Cooperative Acute Stroke Study (ECASS) III trial3 and the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register (SITS-ISTR) 4.5-hour study in October 2008.4 The pooled analysis5 of randomized controlled trials in 2004 and the updated pooled analysis6 in 2010 confirmed the benefit of treatment with intravenous alteplase up to 4.5 hours after stroke. There was no statistically significant benefit observed after 4.5 hours; however, 95% CIs for odds ratios (ORs) indicate that a benefit may exist up to 6 hours after stroke onset. An increased mortality rate was observed when treatment was initiated after 4.5 hours. registering of unselected patients treated with thrombolysis for acute ischemic stroke. The SITS-ISTR centers are committed to registering all consecutive stroke patients treated with thrombolysis, whether treated on- or off-label. We aimed to identify patients treated off-label within 4.5 to 6 hours (271-360 minutes) and recorded in the SITS-ISTR and to compare their outcomes with the outcomes of patients treated within 3 hours (≤180 minutes). We also aimed to update the comparison of outcomes between patients treated within 3 to 4.5 hours (181-270 minutes) and patients treated within 3 hours.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lees, Professor Kennedy
Authors: Ahmed, N., Kellert, L., Lees, K.R., Mikulik, R., Tatlisumak, T., and Toni, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:JAMA Neurology
ISSN:2168-6149
ISSN (Online):2168-6157

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