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Fibrinolytic therapy is the most common reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI), particularly in smaller centers. Previous studies evaluated the relation between time to treatment and outcomes when few patients were treated within 30 minutes of hospital arrival and many did not receive modern adjunctive medications. To quantify the impact of a delay in door-to-needle time on mortality in a recent and representative cohort of patients with STEMI, a cohort of 62,470 patients with STEMI treated using fibrinolytic therapy at 973 hospitals that participated in the National Registry of Myocardial Infarction from 1999 to 2002 was analyzed. Hierarchical models were used to evaluate the independent effect of door-to-needle time on in-hospital mortality. In-hospital mortality was lower with shorter door-to-needle times (2.9% for < or =30 minutes, 4.1% for 31 to 45 minutes, and 6.2% for >45 minutes; p <0.001 for trend). Compared with those experiencing door-to-needle times < or =30 minutes, adjusted odd ratios (ORs) of dying were 1.17 (95% confidence interval [CI] 1.04 to 1.31) and 1.37 (95% CI 1.23 to 1.52; p for trend <0.001) for patients with door-to-needle times of 31 to 45 and >45 minutes, respectively. This relation was particularly pronounced in those presenting within 1 hour of symptom onset to presentation time (OR 1.25, 95% CI 1.01 to 1.54; OR 1.54, 95% CI 1.27 to 1.87, respectively; p for trend <0.001). In conclusion, timely administration of fibrinolytic therapy continues to significantly impact on mortality in the modern era, particularly in patients presenting early after symptom onset.