Apostolos Safouris

Risk of Symptomatic Intracerebral Hemorrhage After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke and High Cerebral Microbleed Burden: A Meta-analysis.

IMPORTANCE Cerebral microbleeds (CMBs) have been established as an independent predictor of cerebral bleeding. There are contradictory data regarding the potential association of CMB burden with the risk of symptomatic intracerebral hemorrhage (sICH) in patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT). OBJECTIVE To investigate the association of high CMB burden (>10 CMBs on a pre-IVT magnetic image resonance [MRI] scan) with the risk of sICH following IVT for AIS. DATA SOURCES Eligible studies were identified by searching Medline and Scopus databases. No language or other restrictions were imposed. The literature search was conducted on October 7, 2015. This meta-analysis has adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) proposal. STUDY SELECTION Eligible prospective study protocols that reported sICH rates in patients with AIS who underwent MRI for CMB screening prior to IVT. DATA EXTRACTION AND SYNTHESIS The reported rates of sICH complicating IVT in patients with AIS with pretreatment MRI were extracted independently for groups of patients with 0 CMBs (CMB absence), 1 or more CMBs (CMB presence), 1 to 10 CMBs (low to moderate CMB burden), and more than 10 CMBs (high CMB burden). An individual-patient data meta-analysis was also performed in the included studies that provided complete patient data sets. MAIN OUTCOMES AND MEASURES Symptomatic intracerebral hemorrhage based on the European Cooperative Acute Stroke Study-II definition (any intracranial bleed with ≥4 points worsening on the National Institutes of Health Stroke Scale score). RESULTS We included 9 studies comprising 2479 patients with AIS. The risk of sICH after IVT was found to be higher in patients with evidence of CMB presence, compared with patients without CMBs (risk ratio [RR], 2.36; 95% CI, 1.21-4.61; P = .01). A higher risk for sICH after IVT was detected in patients with high CMB burden (>10 CMBs) when compared with patients with 0 to 10 CMBs (RR, 12.10; 95% CI, 4.36-33.57; P < .001) or 1 to 10 CMBs (RR, 7.01; 95% CI, 3.20-15.38; P < .001) on pretreatment MRI. In the individual-patient data meta-analysis, high CMB burden was associated with increased likelihood of sICH before (unadjusted odds ratio, 31.06; 95% CI, 7.12-135.44; P < .001) and after (adjusted odds ratio, 18.17; 95% CI, 2.39-138.22; P = .005) adjusting for potential confounders. CONCLUSIONS AND RELEVANCE Presence of CMB and high CMB burdens on pretreatment MRI were independently associated with sICH in patients with AIS treated with IVT. High CMB burden may be included in individual risk stratification scores predicting sICH risk following IVT for AIS.

Recurrent Stroke and Patent Foramen Ovale A Systematic Review and Meta-Analysis

Background and Purpose— Recurrent cerebrovascular events are frequent in medically treated patients with patent foramen ovale (PFO), but it still remains unclear whether PFO is a causal or an incidental finding. Further uncertainty exists on whether the size of functional shunting could represent a potential risk factor. The aim of the present study was to evaluate if the presence of PFO is associated with an increased risk of recurrent stroke or transient ischemic attack and to investigate further if this relationship is related to the shunt size. Methods— We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of all available prospective studies reporting recurrent cerebrovascular events defined as cryptogenic stroke and transient ischemic attacks in medically treated patients with PFO diagnosed by echocardiography or transcranial sonography. Results— We identified 14 eligible studies including a total of 4251 patients. Patients with stroke with PFO did not have a higher risk of the combined outcome of recurrent stroke/transient ischemic attack (risk ratio=1.18; 95% confidence interval=0.78–1.79; P=0.43) or in the incidence of recurrent strokes (risk ratio =0.85; 95% confidence interval=0.59–1.22; P=0.37) in comparison with stroke patients without PFO. In addition, PFO size was not associated with the risk of recurrent stroke or transient ischemic attack. We also documented no evidence of heterogeneity across the included studies. Conclusions— Our findings indicate that medically treated patients with PFO do not have a higher risk for recurrent cryptogenic cerebrovascular events, compared with those without PFO. No relation between the degree of PFO and the risk of future cerebrovascular events was identified.

Statin pretreatment is associated with better outcomes in large artery atherosclerotic stroke

Objective: Even though statin pretreatment is associated with better functional outcomes and lower risk of mortality in acute ischemic stroke, there are limited data evaluating this association in acute ischemic stroke due to large artery atherosclerosis (LAA), which carries the highest risk of early stroke recurrence. Methods: Consecutive patients with acute LAA were prospectively evaluated from 7 tertiary-care stroke centers during a 3-year period. Statin pretreatment, demographics, vascular risk factors, and admission and discharge stroke severity were recorded. The outcome events of interest were neurologic improvement during hospitalization (quantified as the relative decrease in NIH Stroke Scale score at discharge in comparison to hospital admission), favorable functional outcome (FFO) (defined as modified Rankin Scale score of 0–1), recurrent stroke, and death at 1 month. Statistical analyses were performed using univariable and multivariable Cox regression models adjusting for potential confounders. All analyses were repeated following propensity score matching. Results: Statin pretreatment was documented in 192 (37.2%) of 516 consecutive patients with LAA (mean age: 65 ± 13 years; 60.8% men; median NIH Stroke Scale score: 9 points, interquartile range: 5–18). Statin pretreatment was associated with greater neurologic improvement during hospitalization and higher rates of 30-day FFO in unmatched and matched (odds ratio for FFO: 2.44; 95% confidence interval [CI]: 1.07–5.53) analyses. It was also related to lower risk of 1-month mortality and stroke recurrence in unmatched and matched analyses (hazard ratio for recurrent stroke: 0.11, 95% CI: 0.02–0.46; hazard ratio for death: 0.24, 95% CI: 0.08–0.75). Conclusion: Statin pretreatment in patients with acute LAA appears to be associated with better early outcomes regarding neurologic improvement, disability, survival, and stroke recurrence.

Safety of early endarterectomy in patients with symptomatic carotid artery stenosis: an international multicenter study

Although the latest recommendations suggest that carotid endarterectomy (CEA) should be performed in symptomatic carotid artery stenosis (sCAS) patients within 2 weeks of the index event, only a minority of patients undergo surgery within the recommended time‐frame. The aim of this international multicenter study was to prospectively evaluate the safety of early CEA in patients with sCAS in everyday clinical practice settings.

Safety of intravenous thrombolysis for acute ischemic stroke in specific conditions

Introduction: Intravenous administration of tissue-type plasminogen activator (IV-tPA) remains the only approved therapy that may reverse neurological deficit in patients with acute ischemic stroke (AIS). During the past 20 years, accumulating real-word experience have provided additional information regarding its safety and efficacy in various clinical settings that were originally considered as contraindications for systemic thrombolysis. Areas covered: In this narrative review, we address the safety of intravenous thrombolysis (IVT) in specific conditions: dissection of the aortic arch of extracranial and intracranial arteries, concomitant presence of unruptured intracranial aneurysms, arteriovenous malformations and dural fistulas, co-existing brain tumors as well as in conditions mimicking AIS. The review systematically evaluates the safety of off-label use of IVT and summarizes data from case reports of uncommon complications of systemic thrombolysis administration in the setting of acute cerebral ischemia. Expert opinion: The present narrative review summarizing 20 years of clinical experience with IVT for AIS highlights that many of the current guidelines and protocols should be adjusted to accommodate recent data from registries and real-world experience underscoring the safety of IVT in numerous conditions of AIS that were originally considered as relative or absolute contraindications for administration of IV-tPA.

Mechanical thrombectomy for emergent large vessel occlusion: A critical appraisal of recent randomized controlled clinical trials

After numerous attempts to prove efficacy for endovascular treatment of ischemic stroke, a series of recent randomized controlled clinical trials (RCTs) established fast mechanical thrombectomy (MT) as a safe and effective novel treatment for emergent large vessel occlusion (ELVO) in the anterior cerebral circulation.

Novel oral anticoagulants for the secondary prevention of cerebral ischemia: a network meta-analysis.

Background: Novel oral anticoagulants (NOACs) have shown to be both safe and effective for ischemic stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). We conducted a network meta-analysis (NMA) using published data from secondary prevention subgroups of different phase III randomized clinical trials (RCTs) comparing individual NOACs with warfarin. Methods: Eligible studies were identified by searching MEDLINE and SCOPUS and the Cochrane Central Register of Controlled Trials databases. First, we conducted a pairwise meta-analysis for each pairwise comparison, and then we performed NMA to combine direct and indirect evidence for any given pair of treatments. The comparative effects of all NOACs against warfarin were ranked with the surface under the cumulative ranking (SUCRA) curve for each outcome. Results: We identified four RCTs (including 15,240 patients) comparing individual NOACs (apixaban, dabigatran, rivaroxaban) with warfarin. Using indirect evidence, dabigatran was related to a significantly lower risk of hemorrhagic stroke compared with rivaroxaban [risk ratio (RR) 0.28; 95% confidence interval (CI) 0.11–0.75], while rivaroxaban was associated with a significantly lower risk of major gastrointestinal bleeding compared with dabigatran (RR 0.14; 95% CI 0.03–0.74). We also performed clustered ranking plot for the primary efficacy and safety endpoints to identify the treatment with the probably best benefit-to-risk ratio profile. Conclusions: The three NOACs showed differences in terms of safety and efficacy for secondary stroke prevention in NVAF. Our findings can serve only as hypothesis generation and require independent confirmation in head-to-head RCTs, owing to the sparse available evidence and increased uncertainty in both indirect effect estimates and ranking of treatments.

Endovascular reperfusion therapies for acute ischemic stroke: dissecting the evidence

ABSTRACT Background: Ischemic stroke is a major cause of death and disability and intravenous thrombolysis has been the only approved acute reperfusion therapy (RT) for many years. Methods: Seven randomized-controlled clinical trials (RCTs) evaluating the safety and efficacy of endovascular therapy in patients with acute ischemic stroke (AIS) due to emergent large vessel occlusion (ELVO) have been recently published. Results: These studies have changed the treatment paradigm by establishing mechanical thrombectomy (MT) as the most effective acute stroke therapy for improving functional outcome in anterior circulation ELVO with a NNT of 6. Conclusions: The present review will critically evaluate the results of these RCTs and of the existing meta-analyses investigating the safety and efficacy of endovascular therapy for AIS. Points of debate such as acute stroke imaging, posterior circulation stroke and general anesthesia will be addressed. We will also discuss health policies aiming to increase the availability of endovascular treatment for stroke patients.

Rivaroxaban presents a better pharmacokinetic profile than dabigatran in an obese non-diabetic stroke patient.

Novel oral anticoagulants (NOACs) are the recent therapeutic breakthrough in the thromboprophylaxis of non-valvular atrial fibrillation (NVAF). There are currently three different molecules approved for NVAF: dabigatran, rivaroxaban and apixaban. All three agents have demonstrated at least non-inferiority at major clinical endpoints compared to warfarin with their major advantage being the fixed-dose regimen that necessitates no regular blood tests and protects patients from the disastrous effects of infra-therapeutic (embolism) or supratherapeutic (hemorrhage) anticoagulation. VKAs have been notorious for their interindividual variability and intraindividual variability in attaining effective plasma concentrations as well as their frequent drug and food interactions that impose regular International Normalized Ratio (INR) and dose adjustments. The idea of a fixed-dose regimen anticoagulation that would apply to most patients (excluding those with renal insufficiency or concomitant treatment with specific drugs that influence NOAC levels) was warmly received by the clinicians worldwide with rapid endorsement of the new agents in clinical practice. It is generally accepted that, with the exception of emergency situations where the effect of NOACs on anticoagulation should be assessed, there is no place for NOAC level testing in everyday clinical practice. However, a non-diabetic patientweighing153kgwas reported to present an ischemic stroke despite treatment with dabigatran due to non-therapeutic drug levels [1]. We present the case of a 67-year-oldman that presentedwith ischemic stroke due to previously unknown NVAF. He was started on dabigatran 150 mg bid ten days post ictus. His weight was 124 kg and his height 177 cm (Body Mass Index 39.6 kg/m). Glycosylated hemoglobin was 5.8%. Creatinine clearance after 24-hour urine collection was 132 ml/min (normal range 80–120 ml/min). A week after treatment initiation we have tested dabigatran levels using the Hemoclot® thrombin inhibitor assay [2] before the morning dose, 2, 4 and 6 h after witnessed medication intake. We observed that the patient never reached the interquartile range for Cmax and was most of time below the interquartile range of Ctrough [3]. The patient was on bisoprolol and atorvastatin, neither of which has been shown to interact with dabigatran levels. We have substituted dabigatran with rivaroxaban 20 mg qd. Five days after treatment initiation, rivaroxaban concentrations measured with DiXal® Direct factor Xa Inhibitor [4] were found within the interquartile range for therapeutic peak and trough levels suggesting effective anticoagulation (Table 1). The safety of anticoagulation with NOACs has recently received increased attention in low-weight patients because of perceived fear of increased hemorrhagic complications but anticoagulation in obese patients remains a real-life therapeutic challenge in different anticoagulant treatments for various indications [5]. In a sub-group analysis of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study, dabigatran showed decreased trough concentrations with

Statin Pretreatment and Microembolic Signals in Large Artery Atherosclerosis

Objective— Although statin pretreatment (SP) is associated with better outcomes in patients with acute cerebral ischemia after an ischemic stroke/transient ischemic attack, data on the underlying mechanism of this beneficial effect are limited. Approach and Results— We sought to evaluate the potential association between SP and microembolic signal (MES) burden in acute cerebral ischemia because of large artery atherosclerosis (LAA). We prospectively evaluated consecutive patients with first-ever acute cerebral ischemia because of LAA in 3 tertiary stroke centers over a 2-year period. All patients underwent continuous 1-hour transcranial Doppler monitoring of the relevant vessel at baseline (⩽24 hours). SP was recorded and dichotomized as high dose or low-to-moderate dose. SP was documented in 43 (41%) of 106 LAA patients (mean age, 65.4±10.3 years; 72% men; low-to-moderate dose, 32%; high dose, 8%). There was a significant (P=0.022) dose-dependent effect between SP and MES prevalence: no SP (37%), SP with low-to-moderate dose (18%), and SP with high dose (0%). Similarly, a significant (P=0.045) dose-dependent effect was documented between SP and MES burden: no SP (1.1±1.8), SP with low-to-moderate dose (0.7±1.6), and SP with high dose (0±0). In multivariable logistic regression analysis adjusting for demographics, vascular risk factors, location of LAA, stroke severity, and other prevention therapies, SP was associated with lower likelihood of MES presence (odds ratio, 0.29; 95% confidence interval, 0.09–0.92; P=0.036). In addition, SP was found also to be independently related to higher odds of functional improvement (common odds ratio, 3.33; 95% confidence interval, 1.07–10.0; P=0.037). Conclusions— We found that SP in patients with acute LAA is related with reduced MES presence and lower MES burden with an apparently dose-dependent association.