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Background: The concept and tools of oral anticoagulation (OAC) therapy for preventing stroke in patients with non-valvular atrial fibrillation (NVAF) and their use as part of an acute treatment regimen in patients experiencing large-vessel occlusive stroke have grossly changed in the last 10 years. The aim of this study was therefore to evaluate the changes in reperfusion therapy and the clinical outcomes in acute ischemic stroke (AIS) patients with NVAF during a six-year time period.Methods: From March 2011 to March 2017, consecutive patients with AIS with NVAF who were admitted to our department were retrospectively analyzed. Patients were divided into three groups according to the year of their initial visit: 2011-2012 (n=136), 2013-2014 (n=206), and 2015-2016 (n=204). Reperfusion therapy including intravenous thrombolysis and endovascular therapy, and functional outcome, were compared between the three time periods.Results: The rate of reperfusion therapy increased steadily from 19.9% in 2011-2012 to 42.7% in 2015-2016 (P < 0.0001). Parenchymal hematoma (PH) occurrence increased slightly from 5.9% in 2011-2012 to 9.8% in 2015-2016, but there was no significant difference (P = 0.4301). Although there was no difference with respect to National Institutes of Health Stroke Scale (NIHSS) score at admission between the 2011-2012 and 2015-2016 groups (8 vs. 7, P = 0.3926), and CHA2DS2-VASc score was significantly higher in 2015-2016 compared with in 2011-2012 (4 vs 3, P = 0.0062), and discharge NIHSS score in 2015-2016 was significantly lower compared with that in 2011-2012 (2 vs. 4; P = 0.0093). The percentage of modified Rankin Scale 0-1 upon discharge was significantly higher in patients treated with reperfusion therapy than in those who were treated without it, among moderate-severe stroke patients (initial NIHSS ≥ 8) (15.4 vs. 2.8%, P = 0.0002). Moreover, hospital mortality rate significantly decreased from 11.0% in 2011-2012 to 3.4% in 2015-2016 (P = 0.0167).Conclusions: According to the six-year trend, the use of reperfusion therapy increased steadily and this increase appears to be factor in improvement of functional outcome and mortality in patients with AIS with NVAF.