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Background: Novel oral anticoagulants (NOACs) are currently recommended for the secondary prevention of stroke in patients with acute ischemic stroke (AIS) accompanied by atrial fibrillation (AF). However, the impact of NOACs on clinical outcomes in real-world practice remains ambiguous. This study analyzes the trend of clinical events in patients with AF-related AIS and determines how much the introduction of NOACs has mediated this trend., Methods: We identified patients with AIS and AF between January 2011 and December 2019 using a multicenter stroke registry. Annual rates of NOAC prescriptions and clinical events within 1 year were evaluated. The primary outcome was a composite of recurrent stroke, myocardial infarction, and all-cause mortality. To assess the mediation effect of NOACs on the relationship between the calendar year and these outcomes, we used natural effect models and conducted exposure-mediator, exposure-outcome, and mediator-outcome analyses using multivariable regression models or accelerated failure time models, adjusting for potential confounders., Results: Among the 12 977 patients with AF-related AIS, 12 500 (average age: 74.4 years; 51.3% male) were analyzed after excluding cases of valvular AF. Between 2011 and 2019, there was a significant decrease in the 1-year incidence of the primary composite outcome from 28.3% to 21.7%, while the NOAC prescription rate increased from 0% to 75.6%. A 1-year increase in the calendar year was independently associated with delayed occurrence of the primary outcome (adjusted time ratio, 1.10 [95% CI, 1.07-1.14]) and increased NOAC prescription (adjusted odds ratio, 2.20 [95% CI, 2.14-2.27]). Increased NOAC prescription was associated with delayed occurrence of the primary outcome (adjusted time ratio, 3.82 [95% CI, 3.17 to 4.61]). Upon controlling for NOAC prescription (mediator), the calendar year no longer influenced the primary outcome (adjusted time ratio, 0.97 [95% CI, 0.94-1.00]). This suggests that NOAC prescription mediates the association between the calendar year and the primary outcome., Conclusions: Our study highlights a temporal reduction in major clinical events or death in Korean patients with AF-related AIS, mediated by increased NOAC prescription, emphasizing NOAC use in this population., Competing Interests: Disclosures Dr Bae reports grants from Astrazeneca, Bayer Korea, Bristol Myers Squibb, Bristol Myers Squibb Korea, Chong Gun Dang Pharmaceutical Corp, Dong-A ST, Jeil Pharmaceutical Co, Ltd, Korean Drug Co, Ltd, SAMJIN Pharm, Takeda Pharmaceuticals Korea Co, Ltd, and Yuhan Corporation, and personal fees from Amgen Korea, Hanmi Pharmaceutical Co, Ltd, Otsuka Korea, SK Chemicals, and Viatris Korea outside the submitted work. Dr Gorelick received consultative fees for an expert opinion in a medical-legal matter related to stroke in atrial fibrillation.

Background: Optimal antithrombotic regimens to prevent recurrent stroke in patients with ischemic stroke due to atrial fibrillation (AF) and atherosclerotic large-vessel stenosis remain unknown., Aims: This study aimed to evaluate the effect of multiple antithrombotic therapies on outcomes at 1 year after ischemic stroke due to two or more causes., Methods: We identified 862 patients with ischemic stroke due to AF and large artery atherosclerosis from the linked data. These patients were categorized into three groups according to antithrombotic therapies at discharge: (1) antiplatelets, (2) oral anticoagulants (OAC), and (3) antiplatelets plus OAC. The study outcomes were recurrent ischemic stroke, composite outcomes for cardiovascular events, and major bleeding after 1 year. Inverse probability of treatment weighting (IPTW) was used to balance the three groups using propensity scores., Results: Among 862 patients, 169 (19.6%) were treated with antiplatelets, 405 (47.0%) were treated with OAC, and 288 (33.4%) were treated with antiplatelets and OAC. After applying IPTW, only OAC had a significant beneficial effect on the 1-year composite outcome (hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.23-0.60, p < 0.001) and death (HR: 0.35, 95% CI: (0.19-0.63), p < 0.001). The combination of antiplatelet agents and OAC group had an increased risk of major bleeding complications (HR: 5.27, 95% CI: (1.31-21.16), p = 0.019). However, there was no significant difference in 1-year recurrent stroke events among the three groups., Conclusion: This study demonstrated that OAC monotherapy was associated with lower risks of composite outcome and death in patients at 1 year after ischemic stroke due to AF and atherosclerotic stenosis. In addition, the combination of an antiplatelet and OAC had a high risk of major bleeding.

Background: We aimed to evaluate covert brain infarction (CBI), frequently encountered during the diagnostic work-up of acute ischemic stroke, as a risk factor for stroke recurrence in patients with atrial fibrillation (AF)., Methods: For this prospective cohort study, from patients with acute ischemic stroke hospitalized at 14 centers between 2017 and 2019, we enrolled AF patients without history of stroke or transient ischemic attack and divided them into the CBI (+) and CBI (-) groups. The 2 groups were compared regarding the 1-year cumulative incidence of recurrent ischemic stroke and all-cause mortality using the Fine and Gray subdistribution hazard model with nonstroke death as a competing risk and the Cox frailty model, respectively. Each CBI lesion was also categorized into either embolic-appearing (EA) or non-EA pattern CBI. Adjusted hazard ratios and 95% CIs of any CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were estimated., Results: Among 1383 first-ever stroke patients with AF, 578 patients (41.8%) had CBI. Of these 578 with CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were 61.8% (n=357), 21.8% (n=126), and 16.4% (n=95), respectively. The estimated 1-year cumulative incidence of recurrent ischemic stroke was 5.2% and 1.9% in the CBI (+) and CBI (-) groups, respectively ( P =0.001 by Gray test). CBI increased the risk of recurrent ischemic stroke (adjusted hazard ratio [95% CI], 2.91 [1.44-5.88]) but did not the risk of all-cause mortality (1.32 [0.97-1.80]). The EA pattern CBI only and both CBIs elevated the risk of recurrent ischemic stroke (2.76 [1.32-5.77] and 5.39 [2.25-12.91], respectively), while the non-EA pattern only did not (1.44 [0.40-5.16])., Conclusions: Our study suggests that AF patients with CBI might have increased risk of recurrent stroke. CBI could be considered when estimating the stroke risk in patients with AF.

Background and Purpose: The purpose of this study was to determine whether underweight is associated with poststroke cardiovascular events and whether such association is different according to the presence of atrial fibrillation (AF)., Methods: Patients with acute stroke or transient ischemic attack who were prospectively registered in a multicenter stroke database from April 2008 to July 2020 were analyzed, excluding those aged 75 or older and those who were overweight. We prospectively captured major adverse cardiovascular events (MACE) within one year after stroke. Cox-proportional hazard regression analysis was conducted for each subgroup with or without AF after adjusting for predetermined vascular risk factors and potential confounders., Results: Among 30,912 patients, 1494 (4.8%) cases were underweight and 29,418 (95.2%) cases were normal weight. The cumulative event rate of 1-year MACE was higher in the underweight group (9.0%) than in the normal weight group (5.6%). In Cox-proportional regression, underweight was associated with significantly higher MACE (adjusted hazard ratio [HR]: 1.62, 95% confidence interval [CI]: 1.26-2.09) and recurrent stroke (adjusted HR: 1.42, 95% CI: 1.02-1.98) in all study patients. In patients with AF, the risk of MACE for the underweight group was not significantly increased. In contrast, in patients without AF, the underweight group had a consistently higher risk of MACE (adjusted HR: 1.66, 95% CI: 1.25-2.22) and recurrent stroke (adjusted HR: 1.50, 95% CI: 1.05-2.14)., Conclusions: Underweight increased the risk of MACE and recurrent stroke within one year after acute stroke, especially in stroke without AF., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We investigated a multicenter registry to identify estimated event rates according to CHA2DS2-VASc scores in patients with acute ischemic stroke (AIS) and atrial fibrillation (AF). The additional effectiveness of antiplatelets (APs) plus oral anticoagulants (OACs) compared with OACs alone considering the CHA2DS2-VASc scores was also explored. This study retrospectively analyzed a multicenter stroke registry between Jan 2011 and Nov 2017, identifying patients with acute ischemic stroke with AF. The primary outcome event was a composite of recurrent stroke, myocardial infarction, and all-cause mortality within 1 year. A total of 7395 patients (age, 73 ± 10 years; men, 54.2%) were analyzed. The primary outcome events at one year ranged from 5.99% (95% CI 3.21-8.77) for a CHA2DS2-VASc score of 0 points to 30.45% (95% CI 24.93-35.97) for 7 or more points. After adjustments for covariates, 1-point increases in the CHA2DS2-VASc score consistently increased the risk of primary outcome events (aHR 1.10 [1.06-1.15]) at 1-year. Among OAC-treated patients at discharge (n = 5500), those treated with OAC + AP (vs. OAC alone) were more likely to experience vascular events, though among patients with a CHA2DS2-VASc score of 5 or higher, the risk of primary outcome in the OAC + AP group was comparable to that in the OAC alone group (P int  = 0.01). Our study found that there were significant associations of increasing CHA2DS2-VASc scores with the increasing risk of vascular events at 1-year in AIS with AF. Further study would be warranted.

We investigated the effectiveness of adding antiplatelet (AP) to oral anticoagulant (OAC) treatment versus OAC treatment alone in patients with AIS with atrial fibrillation (AF) and significant large artery steno-occlusion (LASO). This study is a retrospective analysis of a nationwide, prospective, multicenter stroke registry between April 2008 and November 2017. Patients with acute (within 48 h of onset) and mild-to-moderate (NIHSS score ≤ 15) stroke with AF and concomitant LASO were identified. Antithrombotic regimens at discharge were categorized into OAC alone or OAC + AP. The primary outcome event was a composite of recurrent stroke, myocardial infarction, and all-cause mortality within 3 months of stroke. Among the 2553 patients (age, 73 ± 10 years; men, 50.4%), 78.8% were treated with OAC alone, and 21.2% were treated with OAC + AP. The primary outcome events were significantly more common in the OAC + AP group (6.7%) than the OAC alone group (4.3%) (p = 0.02). Weighted Cox proportional hazard analysis showed that OAC + AP increased the risk of 3-month primary outcome events compared with OAC alone (HR, 1.62 [1.06 to 2.46]). A potential interaction between the type of LASO and discharge antithrombotics was suggested (P interaction  = 0.04); unlike in patients with complete occlusion (OAC + AP; HR, 2.00 [1.27-3.15]), OAC + AP was comparable with OAC alone for 3-month primary outcome in patients with moderate-to-severe stenosis (HR, 0.54 [0.17-1.70]). In conclusion, OAC + AP might increase the risk of 3-month outcome events compared with OAC alone in patients with AIS with AF and concomitant LASO. However, the effect of additional AP to OAC might differ according to LASO type.

Background and Purpose- There is a paucity of information about the role of resting heart rate in the prediction of outcome events in patients with ischemic stroke with atrial fibrillation. We aimed to investigate the relationships between the level and variability of heart rate in the acute stroke period and stroke recurrence and mortality after acute ischemic stroke in patients with atrial fibrillation. Methods- Acute patients with ischemic stroke who had atrial fibrillation and were hospitalized within 48 hours of stroke onset were identified from a multicenter prospective stroke registry database. The acute stroke period was divided into early (within 24 hours of hospitalization) and late (72 hours to 7 days from onset) stages, and data on heart rate in both stages were collected. Moreover, the level and variability of heart rate were assessed using mean values and coefficients of variation. Outcome events were prospectively monitored up to 1 year after the index stroke. Results- Among 2046 patients eligible for the early acute stage analysis, 102 (5.0%) had a stroke recurrence, and 440 (21.5%) died during the first year after stroke. A statistically significant nonlinear J-shaped association was observed between mean heart rate and mortality ( P <0.04 for quadratic and overall effect) but not between mean heart rate and stroke recurrence ( P >0.1 for quadratic and overall effect). The nonlinear and overall effects of the coefficients of variation of heart rate were not significant for all outcome variables. The same results were observed in the late acute stage analysis (n=1576). Conclusions- In patients with atrial fibrillation hospitalized for acute ischemic stroke, the mean heart rate during the acute stroke period was not associated with stroke recurrence but was associated with mortality (nonlinear, J-shaped association). The relationships between heart rate and outcomes were not observed with respect to heart rate variability.

Background: We investigated whether left ventricular filling pressure is associated with arterial occlusion in patients with ischemic stroke related to atrial fibrillation (AF)., Methods: Ninety-nine patients with AF-related stroke were included. Left ventricular filling pressure was assessed by E (early mitral inflow velocity)/e' (early diastolic velocity of the mitral valve annulus velocity) ratio based on tissue Doppler echocardiography. Arterial occlusion was evaluated by computed tomography or magnetic resonance angiography. In addition, the presence of a hyperdense middle cerebral artery sign (HMCAS) on noncontrast brain computed tomography, a marker of acute thrombus burden, was assessed. Multiple logistic regression was used to evaluate the association of E/e' with arterial occlusion and the HMCAS., Results: The mean age was 73.2 (±10.2), and 56% were men. Thirty-six (36.4%) patients had arterial occlusion on imaging. E/e' ratios were independently associated with arterial occlusion with an odds ratio of 1.24 (per 1 increase, 95% confidence interval 1.11-1.38). The receiver operating characteristics curve demonstrated that E/e' ratios have an excellent discriminatory capacity in predicting arterial occlusion with an area under the curve of .77 (P < .001). In addition, E/e' ratios were higher in patients with HMCAS than in those without (19.1 versus 14.0, P < .001)., Conclusion: E/e' ratios were associated with arterial occlusion in AF-related stroke and may play a role in identifying patients at high risk of severe stroke., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Anticoagulation effectively prevents cardioembolic stroke in atrial fibrillation (AF) patients, whereas it is less effective than antiplatelet therapy (AT) in noncardioembolic stroke prevention. We hypothesized that the ischemic lesion pattern and vascular patency would differ according to the antithrombotic treatment status in AF patients., Methods: The medical records of 1078 acute ischemic stroke patients with AF were retrospectively reviewed. Patients were classified according to medication at stroke onset: (1) optimal anticoagulation (OAC; international normalized ratio [INR] 1.7-3.0; n = 36); (2) suboptimal anticoagulation (SOAC; INR ≤1.7; n = 134); (3) AT (n = 285); and (4) control (no antithrombotic medication; n = 623). Imaging and clinical variables of each group were compared with that of controls., Results: Small cortical or single subcortical infarctions were more common in the OAC group than in controls (6% vs. 1% and 22% vs. 8%, respectively; standardized residual, 2.4 and 2.8). Multicirculatory infarctions were less common in the OAC group than in controls (0% vs. 11%; standardized residual, -2.0). Obstruction of the corresponding artery was less common in the OAC group than in controls (26.5% vs. 46.5%, P = .02). Initial neurologic severity was lower in the OAC and AT groups than in controls (P = .01 and .03, respectively). OAC and AT were independently associated with favorable functional outcome at 3-months (P = .015 and <.001, respectively)., Conclusions: Ischemic stroke can occur during OAC in AF patients. Small cortical or single subcortical lesions were more common than typical cardioembolic lesion patterns. OAC and AT were protective against severe neurologic deficit and independently associated with favorable outcome, but SOAC was not., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Patients with acute cardioembolic stroke frequently show hemorrhagic transformation (HTr). We attempted to identify predictors of symptomatic HTr in acute ischemic stroke with atrial fibrillation (AF)., Methods: Of the consecutive acute ischemic stroke patients with AF at 12 hospitals in Korea, patients with posterior circulation stroke or thrombolytic therapy were excluded. Immediate anticoagulation was recommended to all patients, except those with: (1) large infarcts, 50% or more of the middle cerebral artery territory, (2) significant HTr on initial imaging, or (3) other safety concerns. Symptomatic HTr was defined as cerebral hemorrhage temporally related to neurological deterioration., Results: Of the 389 included patients (mean age 71 years), 260 (67%) were treated with anticoagulation within 1 week from the onset. Symptomatic HTr occurred in 4.6%. Large infarct (OR 6.38, 95% CI 1.16-35.14), previous hemorrhagic stroke (OR 10.67, 1.77-64.25), and low platelet count (OR per 10(4) increase 0.87, 0.79-0.97) were independent predictors of symptomatic HTr. hsCRP values tended to be higher in patients with symptomatic HTr (p = 0.055)., Conclusions: Caution is needed in anticoagulation treatment of acute cardioembolic stroke patients with a large infarct, previous hemorrhagic stroke, low platelet count, or a high hsCRP level., (Copyright © 2010 S. Karger AG, Basel.)