{"doi":"10.1056/nejmoa0804656","title":"Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke","abstract":"<h4>Background</h4>Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.<h4>Methods</h4>After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.<h4>Results</h4>We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.<h4>Conclusions</h4>As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)","journal":"New England Journal of Medicine","year":2008,"id":4422,"datarank":16.76760168760113,"base_score":8.79346036105272,"endowment":8.79346036105272,"self_citation_contribution":1.319019054157908,"citation_network_contribution":15.448582633443221,"self_endowment_contribution":1.319019054157908,"citer_contribution":15.448582633443221,"corpus_percentile":89.5,"corpus_rank":1911,"citation_count":6590,"citer_count":171,"citers_with_citation_signal":171,"citers_with_endowment":171,"datacite_reuse_total":0,"is_dataset":false,"is_oa":true,"file_count":1,"downloads":16,"has_version_chain":false,"published_date":"2008-09-25","authors":[{"id":45304,"name":"Markku Kaste","orcid":"0000-0001-6557-6412","position":1,"is_corresponding":false},{"id":45305,"name":"Erich Bluhmki","orcid":"0000-0002-3846-7226","position":2,"is_corresponding":false},{"id":45306,"name":"Miroslav Brozman","orcid":null,"position":3,"is_corresponding":false},{"id":45307,"name":"Antoni Dávalos","orcid":"0000-0003-2949-5679","position":4,"is_corresponding":false},{"id":45308,"name":"Donata Guidetti","orcid":"0000-0002-8477-5131","position":5,"is_corresponding":false},{"id":45309,"name":"Vincent Larrue","orcid":"0000-0002-7097-894X","position":6,"is_corresponding":false},{"id":45310,"name":"Kennedy R. Lees","orcid":"0000-0002-9783-1227","position":7,"is_corresponding":false},{"id":45311,"name":"Zakaria Medeghri","orcid":null,"position":8,"is_corresponding":false},{"id":45312,"name":"Thomas Machnig","orcid":null,"position":9,"is_corresponding":false},{"id":45313,"name":"Dietmar Schneider","orcid":null,"position":10,"is_corresponding":false},{"id":45314,"name":"Rüdiger von Kummer","orcid":"0000-0003-0119-4604","position":11,"is_corresponding":false},{"id":45315,"name":"Nils Wahlgren","orcid":"0000-0002-0421-8838","position":12,"is_corresponding":false},{"id":45316,"name":"Danilo Toni","orcid":"0000-0003-2735-8427","position":13,"is_corresponding":false},{"id":45317,"name":"M Brozman","orcid":"0000-0002-2680-538X","position":14,"is_corresponding":false},{"id":45303,"name":"Werner Hacke","orcid":"0000-0002-6951-6182","position":0,"is_corresponding":true}],"reference_count":23,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}