More Than 50 Percent Reduction in LDL Cholesterol in Patients With Target LDL <70 mg/dL After a Stroke.

BACKGROUND: Whether a strategy to target an LDL (low-density lipoprotein) cholesterol <70 mg/dL is more effective when LDL is reduced >50% from baseline rather than <50% from baseline has not been investigated. METHODS: The Treat Stroke to Target trial was conducted in France and South Korea in 61 sites between March 2010 and December 2018. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 mg/dL or 100±10 mg/dL, using statin and/or ezetimibe as needed. We used the results of repeated LDL measurements (median, 5 [2-6] per patient) during 3.9 years (interquartile range, 2.1-6.8) of follow-up. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time-varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event. RESULTS: Among 2860 patients enrolled, patients in the lower target group who had >50% LDL cholesterol reduction from baseline during the trial had a higher baseline LDL cholesterol and a lower LDL cholesterol achieved as compared to patients who had <50% LDL cholesterol reduction (155±32 and 62 mg/dL versus 121±34 and 74 mg/dL, respectively, P<0.001 for both). In the <70 mg/dL target group, patients with >50% LDL reduction had a significant reduction in the primary outcome as compared to the higher target group (hazard ratio, 0.61 [95% CI, 0.43-0.88]; P=0.007) and patients with <50% LDL reduction from baseline had little reduction (hazard ratio, 0.96 [95% CI, 0.73-1.26]; P=0.75). CONCLUSIONS: In this post hoc analysis of the TST trial, targeting an LDL cholesterol of <70 mg/dL reduced the risk of primary outcome compared with 100±10 mg/dL provided LDL cholesterol reduction from baseline was superior to 50%, thereby suggesting that the magnitude of LDL cholesterol reduction was as important to consider as the target level to achieve. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01252875. URL: https://clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke.

BACKGROUND: The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied. METHODS: In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. RESULTS: A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P = 0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups. CONCLUSIONS: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.).

Intracranial Hemorrhage in the TST Trial.

BACKGROUND AND PURPOSE: Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH. METHODS: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of <70 mg/dL or 100±10 mg/dL, using statin or ezetimibe. RESULTS: Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38-4.04] and 2.32/1000 patient-years [95% CI, 1.61-3.03], respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01-6.31], P=0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00-5.62], P=0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH. CONCLUSIONS: Targeting an LDL cholesterol of <70 mg/dL compared with 100±10 mg/dL in patients with atherosclerotic ischemic stroke nonsignificantly increased the risk of ICH. Incident ICHs were not associated with low LDL cholesterol. Uncontrolled hypertension and anticoagulant therapy were associated with ICH which has important clinical implications. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252875; EUDRACT identifier: 2009-A01280-57.

Yield of Dual Therapy With Statin and Ezetimibe in the Treat Stroke to Target Trial.

BACKGROUND: In atherosclerotic stroke, lipid-lowering treatment with a target LDL (low-density lipoprotein) cholesterol of <70 compared with 100±10 mg/dL reduced the risk of subsequent cardiovascular events. This post hoc analysis explored the relative effects of the combination of statin and ezetimibe (dual therapy) and statin monotherapy in achieving the lower LDL cholesterol target and in reducing the risk of major vascular events, as compared with the higher target group. METHODS: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 or 100±10 mg/dL, using statin and/or ezetimibe as needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event. RESULTS: Among 2860 patients enrolled, patients who were on dual therapy during the trial in the lower target group had a higher baseline LDL cholesterol as compared to patients on statin monotherapy (141±38 versus 131±36, respectively, P<0.001). In patients on dual therapy and on statin monotherapy, the achieved LDL cholesterol was 66.2 and 64.1 mg/dL respectively, and the primary outcome was reduced during dual therapy as compared with the higher target group (HR, 0.60 [95% CI, 0.39-0.91]; P=0.016) but not during statin monotherapy (HR, 0.92 [95% CI, 0.70-1.20]; P=0.52), with no significant increase in intracranial bleeding. CONCLUSIONS: In the TST trial (Treat Stroke to Target), targeting an LDL cholesterol of < 70 mg/dL with a combination of statin and ezetimibe compared with 100±10 mg/dL consistently reduced the risk of subsequent stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01252875. URL: clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

Benefit of Targeting a LDL (Low-Density Lipoprotein) Cholesterol <70 mg/dL During 5 Years After Ischemic Stroke.

Background and Purpose- The TST trial (Treat Stroke to Target) evaluated the benefit of targeting a LDL (low-density lipoprotein) cholesterol of <70 mg/dL to reduce the risk of cardiovascular events in 2860 patients with ischemic stroke with atherosclerotic stenosis of cerebral vasculature or aortic arch plaque >4 mm, in a French and Korean population. The follow-up lasted a median of 5.3 years in French patients (similar to the median follow-up time in the SPARCL trial [Stroke Prevention by Aggressive Reduction in Cholesterol Level]) and 2.0 years in Korean patients. Exposure duration to statin is a well-known driver for cardiovascular risk reduction. We report here the TST results in the French cohort. Methods- One thousand seventy-three French patients were assigned to <70 mg/dL (1.8 mmol/L) and 1075 to 100±10 mg/dL (90-110 mg/dL, 2.3-2.8 mmol/L). To achieve these goals, investigators used the statin and dosage of their choice and added ezetimibe on top if needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization and vascular death. Results- After a median follow-up of 5.3 years, the achieved LDL cholesterol was 66 (1.69 mmol/L) and 96 mg/dL (2.46 mmol/L) on average, respectively. The primary end point occurred in 9.6% and 12.9% of patients, respectively (HR, 0.74 [95% CI, 0.57-0.94]; P=0.019). Cerebral infarction or urgent carotid revascularization following transient ischemic attack was reduced by 27% (P=0.046). Cerebral infarction or intracranial hemorrhage was reduced by 28% (P=0.023). The primary outcome or intracranial hemorrhage was reduced by 25% (P=0.021). Intracranial hemorrhages occurred in 13 and 11 patients, respectively (HR, 1.17 [95% CI, 0.53-2.62]; P=0.70). Conclusions- After an ischemic stroke of documented atherosclerotic origin, targeting a LDL cholesterol of <70 mg/dL during 5.3 years avoided 1 subsequent major vascular event in 4 (number needed to treat of 30) and no increase in intracranial hemorrhage. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252875.

The Pathophysiology of Watershed Infarction: A Three-Dimensional Time-of-Flight Magnetic Resonance Angiography Study.

BACKGROUND: Most of the time, watershed infarcts (WIs) involve steno-occlusive carotid disease. The pathophysiological mechanism could be predicted by their pattern: internal WIs (IWIs) are thought to be due to hemodynamic impairment in contrast to cortical WIs (CWIs), which are more likely to be caused by microembolic phenomena. We used a 3D time-of-flight (TOF) magnetic resonance angiography (MRA) study to assess this hypothesis. METHODS: In 45 consecutive patients with a recent WI and ipsilateral cervical carotid stenosis, clinical and radiological data were obtained retrospectively. 3D TOF MRA were analyzed both qualitatively and quantitatively (internal carotid and anterior, middle and posterior cerebral arteries). Then, 2 groups were determined depending on their radiological patterns: WIs with (IWI+) or without (IWI-) an internal watershed. RESULTS: Thirty-two of the 45 patients (71%) had IWIs that were or were not associated with CWIs (IWI+), while 13 patients (29%) had only CWIs (IWI-). There was no significant relationship between the radiological pattern and the demographic data, the cardiovascular risk factors, or the degree of stenosis. However, IWI+ patients more frequently had motor weakness (P = .03) than CWI patients. An ipsilateral reduced middle cerebral artery intensity on 3D TOF MRA in both qualitative and quantitative analyses was significantly associated with IWI+. Instead within IWI-, no significantly reduced signal intensity was found. CONCLUSION: These findings originally support the view that IWIs are mainly caused by a hemodynamic impairment related to carotid stenosis, whereas CWIs are mostly due to a microembolic mechanism. 3D TOF MRA, which gives pertinent information on pathophysiology on IWIs, can help in decision making.

Changes in Activated Thrombin-Activatable Fibrinolysis Inhibitor Levels Following Thrombolytic Therapy in Ischemic Stroke Patients Correlate with Clinical Outcome.

BACKGROUND AND PURPOSE: Thrombin-activatable fibrinolysis inhibitor (TAFI) activation following thrombolysis may affect thrombolysis effectiveness in acute ischemic stroke (AIS). To support this hypothesis, we propose to study the relationship between TAFI consumption, activated/inactivated TAFI (TAFIa/ai) and stroke severity and outcome in 2 groups of AIS patients, one treated and one untreated with intravenous recombinant tissue type plasminogen activator (rt-PA). METHODS: In this prospective, longitudinal, multicenter, observational study, we aimed to study the association between TAFIa/ai and stroke outcome. TAFI levels were sequentially measured in patients treated with intravenous rt-PA thrombolysis (T), and in patients not given any thrombolytic therapy (NT). Baseline reference values were established in healthy subjects matched for age and gender. The National Institutes of Health Stroke Scale (NIHSS) score assessed at baseline and on day 2 was dichotomized into 2 severity groups (0-7 vs. >7). The modified Rankin Scale (mRS) score at day 90 was dichotomized for favorable (0-1) and unfavorable (2-6) outcomes. RESULTS: A total of 109 patients were included, with 41 receiving rt-PA. At admission, patients had higher TAFIa/ai levels than reference. A significant increase in TAFIa/ai levels was observed at the end of thrombolysis (mean change from baseline of 963%) and lasted up to 4 h (191%). Higher TAFIa/ai levels were associated with a more severe day 2 NIHSS score (p = 0.0098 at T2h post thrombolysis) and an unfavorable mRS score from T48h (p = 0.0417) to day 90 (p = 0.0046). In NT patients, higher TAFIa/ai levels at admission were associated with a more severe stroke, as assessed by day 2 NIHSS score (p = 0.0026) and mRS score (p = 0.0003). CONCLUSION: These data demonstrate a consistent relationship between TAFI levels and early clinical severity during rt-PA treatment.

Long-term follow-up study of endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis trial.

BACKGROUND AND PURPOSE: We aimed at comparing the long-term benefit-risk balance of carotid stenting versus endarterectomy for symptomatic carotid stenosis. METHODS: Long-term follow-up study of patients included in Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis (EVA-3S), a randomized, controlled trial of carotid stenting versus endarterectomy in 527 patients with recently symptomatic severe carotid stenosis, conducted in 30 centers in France. The main end point was a composite of any ipsilateral stroke after randomization or any procedural stroke or death. RESULTS: During a median follow-up of 7.1 years (interquartile range, 5.1-8.8 years; maximum 12.4 years), the primary end point occurred in 30 patients in the stenting group compared with 18 patients in the endarterectomy group. Cumulative probabilities of this outcome were 11.0% (95% confidence interval, 7.9-15.2) versus 6.3% (4.0-9.8) in the endarterectomy group at the 5-year follow-up (hazard ratio, 1.85; 1.00-3.40; P=0.04) and 11.5% (8.2-15.9) versus 7.6% (4.9-11.8; hazard ratio, 1.70; 0.95-3.06; P=0.07) at the 10-year follow-up. No difference was observed between treatment groups in the rates of ipsilateral stroke beyond the procedural period, severe carotid restenosis (≥70%) or occlusion, death, myocardial infarction, and revascularization procedures. CONCLUSIONS: The long-term benefit-risk balance of carotid stenting versus endarterectomy for symptomatic carotid stenosis favored endarterectomy, a difference driven by a lower risk of procedural stroke after endarterectomy. Both techniques were associated with low and similar long-term risks of recurrent ipsilateral stroke beyond the procedural period. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00190398.

Continuous ECG monitoring for tracking down atrial fibrillation after stroke: Holter or automated analysis strategy?

BACKGROUND: Tracking down atrial fibrillation (AF) in the stroke unit is a relevant challenge for the prevention of recurrent AF-related stroke. The optimal terms of use of continuous ECG monitoring (CEM) are unknown. We compared 24-hour routine Holter ECG with two different CEM analysis strategies for AF detection. METHODS: We prospectively enrolled consecutive ischemic stroke patients. All AF-naïve patients received CEM during hospitalization. Two methods for reading CEM data were compared: manual analysis using the Holter function (hCEM) and semiautomated analysis using software (aCEM). The McNemar test was used to compare AF detection rates. RESULTS: Of the 362 patients included, 58 (16.0%) were non-AF-naïve patients and 304 were AF-naïve patients. AF-Naïve patients underwent CEM with a median duration of 5.3 days (3.4-9.7). We detected 22 new AF cases (7.2%) with first-24-hour hCEM, 31 (10.2%) with aCEM, and 42 (13.8%) with hCEM. hCEM and aCEM both significantly increased the AF detection rate compared to first-24-hour hCEM. hCEM detected more new AF cases than aCEM (+3.6%, p = 0.003). CONCLUSIONS: In stroke patients, early and prolonged aCEM and hCEM both increase the AF detection rate compared to first-24-hour hCEM. hCEM gives the best AF detection rate. We suggest that in aCEM, detection based only on the ventricular rhythm analysis explains its lower specificity and sensitivity.

Optimal timing and duration of continuous electrocardiographic monitoring for detecting atrial fibrillation in stroke patients.

BACKGROUND: Several studies have suggested that after ischemic stroke, continuous electrocardiographic (ECG) monitoring (CEM) increases the atrial fibrillation (AF) detection rate. However, optimal CEM terms of use are not clear. The aim of our study was to evaluate the usefulness of CEM in detecting AF and define optimal terms of the use of CEM. METHODS: We prospectively enrolled consecutive patients with acute ischemic stroke who were admitted to the stroke unit without AF on baseline ECG. We compared 2 strategies of AF detection: the first using CEM and the second with routine clinical practice (24-hour Holter ECG and additional ECGs). Adjusted odds ratios for the association between AF diagnosis and the use of CEM stratified by monitoring duration were calculated using multivariate logistic regression analysis. RESULTS: Of the 1166 patients included, 220 (18.87%) had AF on baseline ECG and were excluded. Of the 946 remaining patients, 592 underwent CEM. The prevalence of AF using CEM was 12.50% compared 2.26% using the routine strategy. After adjustment (demographic data, vascular risk factors, and National Institutes of Health Stroke Scale scores), using CEM increased 5.29 fold the odds of finding AF (95% confidence interval [CI] 2.43-11.55) compared to the routine strategy. The adjusted odds ratio (9.82; 95% CI 3.01-32.07) was maximum for the first day of monitoring and decreased later. Beyond 5 days, CEM usefulness was not significantly higher than the routine strategy. CONCLUSIONS: We suggest that in order to enhance the detection rate of AF, CEM could be generalized in the stroke unit. It must be started early in patients with acute stroke and prolonged over a minimum of 4 days.

Brain natriuretic peptide: a relevant marker to rule out delayed atrial fibrillation in stroke patient.

Detection of new atrial fibrillation (AF) after ischemic stroke is challenging. The aim of the TARGET-AF study was to identify relevant markers for ruling out delayed AF in stroke patients. Early and prolonged Holter electrocardiography (ECG) monitoring during hospitalization was performed systematically in consecutive acute stroke patients naive to AF (no history of AF or no AF on baseline ECG). All clinical and paraclinical data for routine etiologic assessment were collected. The diagnostic value of all parameters significantly associated with AF was assessed by comparison of area under the receiver operating characteristic curve (AUC). Of the 300 stroke patients enrolled (mean age, 62.5 ± 15.5 years; sex ratio: 1.7; mean National Institutes of Health Stroke Scale score, 7.1 ± 7.9, median duration of Holter ECG monitoring, 6.8 days), 52 (17.3%) had newly diagnosed AF. Parameters significantly associated with AF were classified by increasing AUC: anterior circulation localization (AUC, 0.604; 95% confidence interval [CI], 0.546-0.660), P-wave initial force (AUC, 0.608; 95% CI, 0.545-0.669), left atrial dilatation (AUC, 0.657; 95% CI, 0.600-0.711), National Institutes of Health Stroke Scale score (AUC, 0.667; 95% CI, 0.611-0.720), sex (AUC, 0.683; 95% CI, 0.627-0.736), age (AUC, 0.755; 95% CI, 0.707-0.797), CHA2DS2-VASc score (AUC, 0.796; 95% CI, 0.746-0.841), STAF (score for the targeting of AF) score (AUC, 0.842; 95% CI, 0.796-0.882), and plasma brain natriuretic peptide (BNP) level (AUC, 0.868; 95% CI, 0.825-0.904). The use of all parameters combined (AUC, 0.910; 95% CI, 0.872-0.940) was not significantly more efficient in diagnosing AF than BNP alone (P = .248). At the Youden plot, the diagnostic properties for BNP >131 pg/mL were sensitivity, 98.1% (95% CI, 89.7-99.7); specificity, 71.4% (95% CI, 65.3-76.9); and negative predictive value, 99.4% (95% CI, 96.9-99.9). Our data indicate that a BNP level ≤ 131 pg/mL might rule out delayed AF in stroke survivors and could be included in algorithms for AF detection.

Score for the targeting of atrial fibrillation: a new approach to diagnosing paroxysmal atrial fibrillation.

BACKGROUND AND PURPOSE: Detecting paroxysmal atrial fibrillation (PAF) after ischaemic stroke is challenging. There are several methods to increase the detection rate of PAF, but it is first necessary to identify subgroups of patients at risk. In a previous study, we established a clinicoradiologic score that predicts atrial fibrillation (AF) in stroke patients. The purpose of the present study is to validate this score specifically for PAF patients. METHODS: 500 consecutive ischaemic stroke patients were examined in our stroke unit. A blind evaluation of the STAF (score for the targeting of atrial fibrillation) was performed for each patient with or without AF. Firstly, we established the reproducibility of the STAF performance by comparing areas under the receiver operating characteristic curves in the preliminary and present studies. Secondly, to validate the predictive value of the STAF in occult AF, areas under the receiver operating characteristic curves were compared for each type of AF. Thirdly, the best threshold value was calculated. RESULTS: AF was detected in 145 cases including 45% of paroxysmal forms. There is no significant score performance difference (p = 0.192) between the preliminary and prospective cohort areas under the receiver operating characteristic curves. This confirms the reproducibility of STAF performance. The area under the receiver operating characteristic curve for the PAF group was 0.907 versus 0.911 for the permanent AF group (p = 0.906). The diagnostic value of the STAF is as good in permanent as paroxysmal AF. In PAF, a STAF ≥ 5 has a sensitivity of 91% and a specificity of 77%. CONCLUSIONS: Due to its reproducibility and predictive value, the STAF can be used by neurologists as part of a novel diagnostic strategy for occult AF.

Impact of Lower Versus Higher LDL Cholesterol Targets on Cardiovascular Events After Ischemic Stroke in Patients With Diabetes.

After an ischemic stroke with evidence of atherosclerosis, lipid-lowering treatment with a target LDL cholesterol of <70 mg/dL compared with 100 ± 10 mg/dL reduced the risk of subsequent cardiovascular events. In this analysis, we explored the effect in the subgroup of patients with diabetes compared with the subgroup without, as well as in those with newly diagnosed diabetes. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned at a 1:1 ratio to a target LDL cholesterol of <70 mg/dL or 100 ± 10 mg/dL using statin or ezetimibe. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and death resulting from vascular disease. We performed a prespecified analysis to evaluate the effect in patients with diabetes. Of 2,860 patients enrolled, 643 had diabetes at baseline, with a mean age of 66.2 years and baseline LDL cholesterol of 127 mg/dL, and were followed for a median of 3 years. The primary composite end point occurred in 27 (8.2%) of 328 patients in the lower-target group and in 44 (14.0%) of 315 patients in the higher-target group (adjusted hazard ratio [HR] 0.56; 95% CI 0.34-0.89; P = 0.016). In patients without diabetes, the HR was 0.87 (95% CI 0.66-1.14; P = 0.31; interaction P = 0.15). In those with diabetes, there were three intracranial hemorrhages in both randomization groups (0.9% vs. 1.0%, respectively). Newly diagnosed diabetes occurred in 98 (9.2%) of 1,070 and in 80 (7.4%) of 1,085 patients in the lower- and higher-target groups, respectively (HR 1.27; 95% CI 0.94-1.71; P = 0.11), and baseline higher HbA1c was the unique multivariable predictor. In conclusion, after an ischemic stroke with evidence of atherosclerosis, targeting an LDL cholesterol of <70 mg/dL compared with 100 ± 10 mg/dL consistently reduced the risk of subsequent stroke and other major vascular events in patients with and without diabetes, but the higher risk in those with diabetes yielded a higher absolute risk reduction, with number needed to treat of 17.

Monitoring unfractionated heparin therapy. 4 hour-stability of anti-Xa activity in unspun citrated tubes.

Current guidelines recommend performing laboratory tests aimed at monitoring unfractionated heparin (UFH) treatments within a delay not exceeding 1 to 2 h(s) after sampling when blood is collected into citrated tubes. As such a short delay could be an issue, we evaluated the potential impact of longer delays. For that purpose, two citrated tubes were obtained from patients on UFH: one was centrifuged and tested for anti-Xa activity and aPTT within 1 h after collection (T1 h) and one was stored for 4 h at room temperature (T4 h) before being processed. A total of 123 paired tubes were investigated. Anti-Xa activity was significantly lower at T4 h than at T1 h, with a mean bias, calculated according to Bland-Altman, of 0.05 IU/mL. Considering 0.30 to 0.70 IU/mL as the therapeutic range, there were 12 cases of discrepant test results (9.8%). Most of them being around the lower limit of the therapeutic range had no impact on patients' management. APTT was significantly shortened (p < 0.0001) at T4 h vs. T1 h, with a mean bias of -7.9 s. Considering anti-Xa correlated aPTT therapeutic range, 29 cases of discrepant test results (23.6%) were found, 10% would have induce dosage changes. The concordance between anti-Xa activities measured at T4 h and T1 h was excellent (kappa = 0.813) and good for aPTT (kappa = 0.661). In conclusion, extending the delay between blood collection and measurement of tests prescribed for monitoring UFH therapy up to 4 h was found to lead to a systematic reduction in both anti-Xa activity and aPTT in unspun citrated tubes. As changes at T4 h were limited and had few clinically relevance than the ones observed with aPTT testing, a 4 h-delay was found to be acceptable for anti-Xa activity. The maximum delay for aPTT should remain around 1-2 h as changes were more relevant.

Effect of hyperglycemia on stroke outcome is not homogeneous to all patients treated with mechanical thrombectomy.

OBJECTIVES: Admission hyperglycemia is a penumbra-modifying factor that is associated with poor functional outcome in acute ischemic stroke (AIS) patients treated with intravenous rt-PA and/or mechanical thrombectomy (MT). Insulin therapy has failed to demonstrate a clinical benefit and the question of the patient selection remains under debate. We assessed the relationship between admission glycemia (AG) and functional outcome in AIS patients treated by MT according to both penumbra characteristics and reperfusion status. PATIENTS AND METHODS: We performed a retrospective analysis of a multi-center registry of consecutive AIS (NIHSS ≥ 10) due to middle cerebral artery occlusion treated by MT (± tissue Plasminogen Activator (tPA)). To evaluate the association between AG and the 3-month functional outcome (modified Rankin Scale (mRS) ≤2), univariable and multivariable analyses were used. Subgroup analyses were performed according to both clinical-ASPECTS Mismatch (CAM2) and the complete recanalization (CR) status defined by a mTICI scale (modified Thrombolysis in Cerebral Infarction) 2b/3. RESULTS: 216 AIS patients were included (Median Age: 68.43[58.12-77.95], median NIHSS: 18[15-21]). 104/216 (48.15%) patients had mRS≤2 at 3 months. AG was an independent predictor of functional outcome (/1 g/L OR: 0.10[0.03-0.37]) after adjusting for potential cofounders. Among subgroups formed by combining CAM2 and CR, AG was found to be predictor of functional outcome only in CAM2+/CR+ and specifically when recanalization was early. CONCLUSION: This study highlights the fact that the relationship between AG and prognosis is not homogeneous for all patients and indicates that AG has a deleterious effect on the ischemic penumbra, thus explaining its statistical association with functional outcome. Stroke neuroprotection by targeting hyperglycemia should be considered in acute stroke patients with mismatch and early complete recanalization. More prospective randomized trials are needed to generalize the conclusions.

Score for the targeting of atrial fibrillation (STAF): a new approach to the detection of atrial fibrillation in the secondary prevention of ischemic stroke.

BACKGROUND AND PURPOSE: The high risk of recurrence and comorbidity after a stroke associated with atrial fibrillation (AF) justifies an aggressive diagnostic approach so that anticoagulant treatment can be initiated. METHODS: The clinical and paraclinical characteristics of consecutive ischemic stroke patients with and without documented AF were recorded. Independent predictive factors were then used to produce a predictive grading score for diagnosing AF, derived by logistic regression analysis: Score for the Targeting of Atrial Fibrillation (STAF). RESULTS: STAF, calculated from the sum of the points for the 4 items (possible total score 0 to 8): age >62 years (2 points); NIHSS > or =8 (1 point); left atrial dilatation (2 points); absence of symptomatic intraor extracranial stenosis > or =50%, or clinico-radiological lacunar syndrome (3 points). STAF > or =5 identified patients with AF with a sensitivity of 89% and a specificity of 88%. CONCLUSIONS: STAF can be used as part of a novel and simple strategy for the targeting of AF in the secondary prevention of ischemic stroke. A multicenter study is now required to validate STAF in a larger number of patients.

SURF (stroke with underlying risk of atrial fibrillation): Proposals for a definition.

OBJECTIVES: Diagnosis of occult atrial fibrillation (AF) in stroke patients remains challenging. Several scores predictive of occult AF in stroke patients have been proposed, all based on the positive predictive value of clinical, biological, and radiological parameters, but they failed to modify the management of AF detection after stroke. The aim of this study was to identify a group of Stroke patients with Underlying Risk of Atrial Fibrillation (SURF) excluding stroke patients with low risk of AF. PATIENTS AND METHODS: We enrolled consecutive AF-naive stroke patients without indication of long-term anticoagulation. AF was adjudicated after prolonged Holter ECG and 2 years of follow-up. The negative predictive value (NPV) was determined for each relevant parameter in the acute phase. Firstly, clinico-radiological parameters with NPV > 95% defined the initial exclusion criteria of SURF. Secondly, the ultimate exclusion criterion of SURF was defined by a composite criterion constructed using the beta-coefficient of independent predictive parameters of AF determined by logistic regression. RESULTS: Among 773 AF-naïve patients without indication of anticoagulation, 111(14.4%) AFs were found. Initial SURF exclusion criteria, determined by NPV ≥ 95%, are: symptomatic atherosclerotic stenosis ≥50%, symptomatic arterial dissection or lacunar stroke. The SURF definition was completed by a composite exclusion criterion [Age*10+BNP< = 700] (NPV: 96.8%[92.6-98.9]). In the SURF group, 93/195(47.7%) AFs were diagnosed. CONCLUSIONS: In the SURF group, nearly half of the stroke patients had AF. The criteria used to define such a group are easily obtained in all stroke units, in the acute phase. SURF is a new concept proposal, which aims to improve the effectiveness of AF diagnosis after stroke.

Treat stroke to target trial design: First trial comparing two LDL targets in patients with atherothrombotic strokes.

BACKGROUND: In patients with non-cardio-embolic stroke, atorvastatin 80 mg/day reduced the relative risk of recurrent stroke by 16%, and a post hoc analysis showed that achieving an LDL-c of less than 70 mg/dL reduced the relative risk by 28% as compared to an on-treatment LDL of 100 mg/dL or more. Current guidelines from the French drug agency recommend treating with a statin after an ischaemic stroke to a target of less than 100 mg/dL, but no study directly tested LDL-c targets. The Treat Stroke to Target (TST) trial will compare the efficacy of achieving an LDL-c of less than 70 mg/dL versus an achieved LDL-c of 100 ± 10 mg/dL for secondary prevention in patients with recent ischaemic stroke of atherosclerotic origin.Main hypothesis: An achieved on-treatment LDL-c of less than 70 mg/dL will reduce by 25% the risk of recurrent ischaemic stroke, myocardial infarction, urgent coronary or carotid revascularisation following new symptoms requiring hospitalisation, and vascular death compared with on-treatment LDL-c of 100 ± 10 mg/dL. DESIGN: Patients are randomised to either LDL-c levels, and the investigator who is not blinded can use the lipid-lowering agent of his/her choice available on the market (including statins and ezetimibe), in order to achieve the assigned LDL-c level. To be eligible for enrolment, patients have a recent ischaemic stroke or TIA of atherosclerotic origin with at least one arterial stenosis of a cerebral artery, enrolled between acute phase of the qualifying stroke (once the neurological deficit is stabilised) and three months. The initial planned sample size of 3760 participants followed three years was amended to allow follow-up of all enrolled patients until 385 primary efficacy outcome events have occurred, and no later than 31 December 2019. Patients will be recruited in 76 sites in two countries (France and South Korea) between March 2010 and December 2018 (last included patient followed up to one year). Safety outcomes will include haemorrhagic strokes and new onset diabetes. All primary endpoints will be adjudicated by an endpoint committee, blinded to the assigned LDL-c level. Two sub-studies assess (1) the relative effect of assigned LDL-c levels on occurrence of new atherosclerotic plaque as detected by carotid ultrasound during follow-up, using M'ATH software for repositioning and (2) the genetic and biomarker drivers of recurrent primary endpoints according to assigned LDL-c lowering arm, in atherosclerotic strokes. SUMMARY: The TST trial is evaluating the benefits of achieving an LDL-c less than 70 mg/dL for secondary stroke prevention in ischaemic stroke patients of atherosclerotic origin. Main results are anticipated in 2020 or earlier (ClinicalTrials.gov NCT01252875).

[Acute management and secondary prevention of ischemic stroke]. / Infarctus cérébral: prise en charge en urgence et prévention secondaire.

Stroke is a medical emergency. Intravenous administration of recombinant tissue-type plasminogen activator (rt-PA) within three hours of stroke onset is the only pharmacological treatment proven effective in ischemic stroke. Its efficacy is time dependent. Patients must be carefully selected and treated in dedicated stroke units to reduce the risk of hemorrhage. Early treatment in dedicated stroke units reduces mortality and disability, independent of any specific treatment. Secondary prevention includes antiplatelet therapy and successful control of all risk factors (hypertension, diabetes, tobacco use, and hyperlipidemia). Carotid endarterectomy may be considered if the residual disability is not serious. Lowering blood pressure is beneficial even when initial blood pressure is normal. Lowering LDL-C with statins after ischemic stroke reduces the risk of recurrent stroke and coronary events.