Systemic administration of sunflower oil exerts neuroprotection in a mouse model of transient focal cerebral ischaemia.

OBJECTIVES: Natural products are valuable sources of nutraceuticals for the prevention or treatment of ischemic stroke, a major cause of death and severe disability worldwide. Among the mechanisms implicated in cerebral ischemia-reperfusion damage, oxidative stress exerts a pivotal role in disease progression. Given the high antioxidant potential of most components of sunflower oil, we have explored its effects on ischemic brain injury produced in the mouse by transient occlusion of the middle cerebral artery (MCAo). KEY FINDINGS: Intraperitoneal (i.p.) administration of sunflower oil at doses of 3 ml/kg (48 h, 24 h and 1 h before MCAo) significantly reduced brain infarct volume and oedema assessed 24 h after the insult. This neuroprotective treatment schedule also prevented the elevation of brain lipid peroxidation produced by MCAo-reperfusion injury. By contrast, doses of 0.03 ml/kg of sunflower oil resulted ineffective on both cerebral damage and lipid peroxidation. Although sunflower oil did not affect serum levels of Diacron-reactive oxygen metabolites (d-ROMs), both 0.03 and 3 ml/kg dosing regimens resulted in the preservation of serum biological antioxidant potential (BAP) that was otherwise dramatically reduced 24 h after MCAo. CONCLUSIONS: Sunflower oil represents a promising source of neuroprotective extracts/compounds that can be exploited for the prevention and/or treatment of cerebral ischemia.

Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity.

Evidence for the clinical use of neuroprotective drugs for the treatment of cerebral ischemia (CI) is still greatly limited. Spatial/temporal disorientation and cognitive dysfunction are among the most prominent long-term sequelae of CI. Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa that exerts neuroprotective effects against experimental CI. The present study investigated possible neuroprotective mechanisms of action of CBD on spatial memory impairments that are caused by transient global cerebral ischemia (TGCI) in rats. Hippocampal synaptic plasticity is a fundamental mechanism of learning and memory. Thus, we also evaluated the impact of CBD on neuroplastic changes in the hippocampus after TGCI. Wistar rats were trained to learn an eight-arm aversive radial maze (AvRM) task and underwent either sham or TGCI surgery. The animals received vehicle or 10 mg/kg CBD (i.p.) 30 min before surgery, 3 h after surgery, and then once daily for 14 days. On days 7 and 14, we performed a retention memory test. Another group of rats that received the same pharmacological treatment was tested in the object location test (OLT). Brains were removed and processed to assess neuronal degeneration, synaptic protein levels, and dendritic remodeling in the hippocampus. Cannabidiol treatment attenuated ischemia-induced memory deficits. In rats that were subjected to TGCI, CBD attenuated hippocampal CA1 neurodegeneration and increased brain-derived neurotrophic factor levels. Additionally, CBD protected neurons against the deleterious effects of TGCI on dendritic spine number and the length of dendritic arborization. These results suggest that the neuroprotective effects of CBD against TGCI-induced memory impairments involve changes in synaptic plasticity in the hippocampus.

Effectiveness and Safety of Direct Oral Anticoagulants in the Secondary Stroke Prevention of Elderly Patients: Ljubljana Registry of Secondary Stroke Prevention.

BACKGROUND AND OBJECTIVES: The results of randomised clinical trials (RCTs) on direct oral anticoagulants (DOACs) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) can mostly be applied to primary prevention in relatively young patients, since only a minority of patients included in these trials were receiving DOACs for secondary prevention. The real-life secondary prevention subgroup, comprising mostly elderly and high-risk patients, remains a point of interest where further exploration is needed. Our objective was to explore the effectiveness and safety of DOACs for secondary prevention in the real-life conditions. METHODS: In a six-year (2012-2018) period all consecutive patients with a history of transient ischaemic attack (TIA) or stroke, recorded NVAF and prescription of DOAC, were included in this single-centre registry. Choice of the DOAC and dose was based on the discretion of the attending clinician. Data regarding recurrent stroke/TIA or other embolic events, intracranial haemorrhage, other major bleeding, adherence and potential changes of therapy were collected and analysed. RESULTS: During the study period, 566 patients were prescribed a DOAC for secondary stroke prevention, and follow-up data were available for 510 patients, with an average observational time of 2.6 years. The mean age of patients was 77.9 ± 8.7 years. The mean CHA2DS2-VASc and HAS-BLED scores were 5.1 ± 1.2 and 2.4 ± 0.6, respectively. Dabigatran was prescribed in 66%, apixaban in 21% and rivaroxaban in 13% of patients; 58% of patients were prescribed the reduced dose of DOAC. The overall yearly incidence of recurrent stroke, major bleeding and intracranial bleeding was 1.7%, 1.6% and 0.2%, respectively. Thus, we found similar effectiveness and safety of both standard and reduced dose of DOACs for secondary stroke prevention, compared to the RCT and large registries. CONCLUSIONS: Our real-life data study suggests that secondary stroke prevention with DOACs is as effective and safe as primary prevention, both in standard and reduced doses, in a typical group of patients who are older than patients included in RCTs.

Early Anticoagulation or Antiplatelet Therapy Is Critical in Craniocervical Artery Dissection: Results from the COMPASS Registry.

INTRODUCTION: Craniocervical artery dissection (CeAD) is a leading cause of stroke in the young patient population. Recent studies reported a low rate of major adverse cardiac events (MACEs) in patients with CeAD, with no significant difference between patients randomized to anticoagulation or antiplatelet therapy. OBJECTIVE: To compare the effectiveness of anticoagulation and antiplatelet therapy in patients with CeAD. METHODS: All CeAD patients from 2015 to 2017 were consecutively identified by an electronic medical record-based application and enrolled in this prospective longitudinal registry. CeAD was confirmed by imaging and graded using the Denver scale for blunt cerebrovascular injury. Patients were followed for 12 months for MACE defined as stroke, transient ischemic attack (TIA), or death. RESULTS: The cohort included 111 CeAD patients (age 53 ± 15.9 years, 56% Caucasian, 50% female). CeAD was detected by magnetic resonance (5%), computed tomography (88%), or catheter angiography (7%). CeAD was noted in the carotid (59%), vertebral (39%), and basilar (2%) arteries, 82% of which were extracranial dissections. CeAD was classified as grade I, II, III, and IV in 16, 33, 19, and 32%, respectively. A total of 40% of dissections were due to known trauma. A predisposing factor was noted in the majority (78%) of patients, including violent sneezing (21%), carrying a heavy load (19%), sports/recreational activity (11%), chiropractic manipulation (9%), abrupt/prolonged rotation of head (9%), and prolonged phone use (9%). At presentation, 41% had a stroke, 5% had TIA, 39% had headache, and 36% were asymptomatic. Favorable outcome defined as a modified Rankin Scale score of 0-2 was noted in 68% at 3 months and 71% at 12 months. The rate of MACEs at 3 and 12 months was 11 and 14%, respectively, with more events observed in patients who were not receiving anticoagulation/antiplatelet therapy due to contraindications (p = 0.008). CONCLUSIONS: We report diagnostic characteristics, as well as short- and long-term outcomes of CeAD. A high MACE rate was observed within the first 2 weeks of CeAD diagnosis, notably in patients not initiated on anticoagulation or antiplatelet therapy.

Real-World Direct Comparison of the Effectiveness and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Medicare Beneficiaries With Atrial Fibrillation.

It remains unknown whether the comparative effectiveness of direct oral anticoagulants (DOACs) and warfarin differs between atrial fibrillation patients with and without a history of stroke or transient ischemic attack (TIA). Using 2012 to 2014 Medicare claims data, we identified patients newly diagnosed with AF in 2013 to 2014 who initiated apixaban, dabigatran, rivaroxaban, or warfarin. We categorized patients based on a history of stroke or TIA. We constructed Cox proportional hazard models that included indicator variables for treatment groups, a history of stroke or TIA, and the interaction between them, and controlled for demographics and clinical characteristics. DOACs were generally more effective than warfarin in stroke prevention; however, there were important differences between subgroups defined by a history of ischemic stroke. In particular, the superiority of dabigatran compared with warfarin in ischemic stroke prevention was more pronounced in patients with a history of stroke or TIA (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48 to 0.85) than in patients with no history of stroke or TIA (HR 0.94; 95% CI 0.75 to 1.16; p value for interaction = 0.034). There was no difference in the risk of stroke between apixaban, dabigatran, and rivaroxaban in patients with no history of stroke or TIA. However, in patients with a history of stroke or TIA, the risk of stroke was lower with dabigatran (HR 0.64; 95% CI 0.48 to 0.85) and rivaroxaban (HR 0.70; 95% CI 0.56 to 0.87), compared with apixaban (p value for both interactions <0.05). In conclusion, the comparative effectiveness of DOACs differs substantially between patients with and without a history of stroke or TIA; specifically, apixaban is less effective in patients with a history of stroke or TIA.

Geriatric Elements and Oral Anticoagulant Prescribing in Older Atrial Fibrillation Patients: SAGE-AF.

OBJECTIVES: Oral anticoagulants are the cornerstone of stroke prevention in high-risk patients with atrial fibrillation (AF). Geriatric elements, such as cognitive impairment and frailty, commonly occur in these patients and are often cited as reasons for not prescribing oral anticoagulants. We sought to systematically assess geriatric impairments in patients with AF and determine whether they were associated with oral anticoagulant prescribing. DESIGN: Cross-sectional analysis of baseline data from the ongoing Systematic Assessment of Geriatric Elements in Atrial Fibrillation (SAGE-AF) prospective cohort study. SETTING: Multicenter study with site locations in Massachusetts and Georgia that recruited participants from cardiology, electrophysiology, and primary care clinics from 2016 to 2018. PARTICIPANTS: Participants with AF age 65 years or older, CHA2 DS2 -VASc (congestive heart failure; hypertension; aged ≥75 y [doubled]; diabetes mellitus; prior stroke, transient ischemic attack, or thromboembolism [doubled]; vascular disease; age 65-74; female sex) score of 2 or higher, and no oral anticoagulant contraindications (n = 1244). MEASUREMENTS: A six-component geriatric assessment included validated measures of frailty, cognitive function, social support, depressive symptoms, vision, and hearing. Oral anticoagulant use was abstracted from the medical record. RESULTS: A total of 1244 participants (mean age = 76 y; 49% female; 85% white) were enrolled; 42% were cognitively impaired, 14% frail, 53% pre-frail, 12% socially isolated, and 29% had depressive symptoms. Oral anticoagulants were prescribed to 86% of the cohort. Oral anticoagulant prescribing did not vary according to any of the geriatric elements (adjusted odds ratios [ORs] for oral anticoagulant prescribing and cognitive impairment: OR = .75; 95% confidence interval [CI] = .51-1.09; frail OR = .69; 95% CI = .35-1.36; social isolation OR = .90; 95% CI = .52-1.54; depression OR = .79; 95% CI = .49-1.27; visual impairment OR = .98; 95% CI = .65-1.48; and hearing impairment OR = 1.05; 95% CI = .71-1.54). CONCLUSION: Geriatric impairments, particularly cognitive impairment and frailty, were common in our cohort, but treatment with oral anticoagulants did not differ by impairment status. These geriatric impairments are commonly cited as reasons for not prescribing oral anticoagulants, suggesting that prescribers may either be unaware or deliberately ignoring the presence of these factors in clinical settings. J Am Geriatr Soc 68:147-154, 2019.

Real-World Outcomes of Rivaroxaban Treatment in Patients with Both Nonvalvular Atrial Fibrillation and a History of Ischemic Stroke/Transient Ischemic Attack.

INTRODUCTION: Prior stroke is a risk factor for stroke and bleeding during anticoagulation in patients with atrial fibrillation (AF). Although rivaroxaban is widely prescribed to reduce their risk of stroke in patients with nonvalvular AF (NVAF), the real-world evidence on rivaroxaban treatment is limited. We aimed to examine the outcomes of rivaroxaban treatment in NVAF patients with prior ischemic stroke/transient ischemic attack (TIA) by using the data of the Xarelto Post-Authorization Safety and Effectiveness Study in Japanese -Patients with AF, a prospective, single-arm, observational study. METHODS: The clinical outcomes of 9,578 patients who completed the 1-year follow-up were evaluated. Safety and effectiveness outcomes were compared between patients with and without prior ischemic stroke/TIA. RESULTS: Among the patients, 2,153 (22.5%) had prior ischemic stroke/TIA. They were significantly older and had lower body weight, lower creatinine clearance, higher CHADS2, CHA2DS2-VASc, and modified HAS-BLED scores as compared to those without prior ischemic stroke/TIA. Any bleeding (9.1 vs. 7.2 events per 100 patient-years), major bleeding (2.3 vs. 1.6 events per 100 patient-years), and stroke/non-central nervous system systemic embolism/myocardial infarction (3.4 vs. 1.3 events per 100 patient-years) were more frequent in patients with prior ischemic stroke/TIA. Stepwise regression analysis suggested that body weight of ≤50 kg and diabetes mellitus were predictive of major bleeding in patients with prior ischemic stroke/TIA. CONCLUSIONS: Safety and effectiveness event rates were higher in patients with prior ischemic stroke/TIA than those without. This might be explained by differences in several risk profiles including age, body weight, renal function, and risk scores such as CHADS2 between the groups. Clinicaltrials.gov: NCT01582737.

A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial.

AIMS: Stroke is often a devastating event among patients with heart failure with reduced ejection (HFrEF). In COMMANDER HF, rivaroxaban 2.5 mg b.i.d. did not reduce the composite of first occurrence of death, stroke, or myocardial infarction compared with placebo in patients with HFrEF, coronary artery disease (CAD), and sinus rhythm. We now examine the incidence, timing, type, severity, and predictors of stroke or a transient ischaemic attack (TIA), and seek to establish the net clinical benefit of treatment with low-dose rivaroxaban. METHODS AND RESULTS: In this double-blind, randomized trial, 5022 patients who had HFrEF(≤40%), elevated natriuretic peptides, CAD, and who were in sinus rhythm were treated with rivaroxaban 2.5 mg b.i.d. or placebo in addition to antiplatelet therapy, after an episode of worsening HF. The primary neurological outcome for this post hoc analysis was time to first event of any stroke or TIA. Over a median follow-up of 20.5 (25th-75th percentiles 20.0-20.9) months, 150 all-cause stroke (127) or TIA (23) events occurred (ischaemic stroke in 82% and haemorrhagic stroke in 11% of stroke events). Overall, 47.5% of first-time strokes were either disabling (16.5%) or fatal (31%). Prior stroke, low body mass index, geographic region, and the CHA2DS2-VASc score were predictors of stroke/TIA. Rivaroxaban significantly reduced the primary neurological endpoint of all-cause stroke or TIA compared with placebo by 32% (1.29 events vs. 1.90 events per 100 patient-years), adjusted for the time from index HF event to randomization and stratified by geographic region (adjusted hazard ratio 0.68, 95% confidence interval 0.49-0.94), with a number needed to treat of 164 patients per year to prevent one stroke/TIA event. The principal safety endpoint of fatal bleeding or bleeding into a critical space, occurred at a similar rate on rivaroxaban and placebo (0.44 events vs. 0.55 events per 100 patient-years). CONCLUSIONS: Patients with HFrEF and CAD are at risk for stroke or TIA in the period following an episode of worsening heart failure in the absence of atrial fibrillation. Most strokes are of ischaemic origin and nearly half are either disabling or fatal. Rivaroxaban at a dose of 2.5 mg b.i.d. reduced rates of stroke or TIA compared with placebo in this population. TRIAL REGISTRATION: COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure); ClinicalTrials.gov NCT01877915.

Efficacy of a Discharge Educational Strategy vs Standard Discharge Care on Reduction of Vascular Risk in Patients With Stroke and Transient Ischemic Attack: The DESERVE Randomized Clinical Trial.

Importance: Despite secondary prevention strategies with proven efficacy, recurrent stroke rates remain high, particularly in racial/ethnic minority populations who are disproportionately affected by stroke. Objective: To determine the efficacy of a culturally tailored skills-based educational intervention with telephone follow-up compared with standard discharge care on systolic blood pressure reduction in a multiethnic cohort of patients with mild/moderate stroke/transient ischemic attack. Design, Setting, and Participants: Randomized clinical trial with 1-year follow-up. Participants were white, black, and Hispanic patients with mild/moderate stroke/transient ischemic attack prospectively enrolled from 4 New York City, New York, medical centers during hospitalization or emergency department visit between August 2012 and May 2016. Through screening of stroke admissions and emergency department notifications, 1083 eligible patients were identified, of whom 256 declined to participate and 275 were excluded for other reasons. Analyses were intention to treat. Interventions: The Discharge Educational Strategies for Reduction of Vascular Events (DESERVE) intervention is a skills-based, culturally tailored discharge program with follow-up calls delivered by a community health coordinator. This intervention was developed using a community engagement approach. Main Outcomes and Measures: The primary outcome was systolic blood pressure reduction at 12 months postdischarge. Results: A total of 552 participants were randomized to receive intervention or usual care (281 women [51%]; mean [SD] age, 64.61 [2.9] years; 180 Hispanic [33%], 151 non-Hispanic white [27%], and 183 non-Hispanic black [33%]). At 1-year follow-up, no significant difference in systolic blood pressure reduction was observed between intervention and usual care groups (ß = 2.5 mm Hg; 95% CI, -1.9 to 6.9). Although not powered for subgroup analysis, we found that among Hispanic individuals, the intervention arm had a clinically and statically significant 9.9 mm Hg-greater mean systolic blood pressure reduction compared with usual care (95% CI, 1.8-18.0). There were no significant differences between arms among non-Hispanic white (ß = 3.3; 95% CI, -4.1 to 10.7) and non-Hispanic black participants (ß = -1.6; 95% CI, -10.1 to 6.8). Conclusions and Relevance: Few behavioral intervention studies in individuals who have had stroke have reported clinically meaningful reductions in blood pressure at 12 months, and fewer have focused on a skills-based approach. Results of secondary analyses suggest that culturally tailored, skills-based strategies may be an important alternative to knowledge-focused approaches in achieving sustained vascular risk reduction and addressing racial/ethnic stroke disparities; however, these findings should be tested in future studies. Trial Registration: ClinicalTrials.gov identifier: NCT01836354.

Meta-analysis and trial sequential analysis of local vs. general anaesthesia for carotid endarterectomy.

Controversy exists regarding the best choice of anaesthesia for carotid endarterectomy. We aimed to evaluate the peri-operative outcomes of local vs. general anaesthesia for carotid endarterectomy. We conducted a systematic search of electronic information sources and applied a combination of free text and controlled vocabulary searches adapted to thesaurus headings, search operators and limits in each of the electronic databases. We defined peri-operative stroke, transient ischaemic attack, mortality and myocardial infarction as the primary outcome measures. We identified 12 randomised controlled trials and 21 observational studies reporting a total of 58,212 patients undergoing carotid endarterectomy under local or general anaesthesia. Analysis of observational studies demonstrated that local anaesthesia was associated with a significantly lower incidence of stroke (odds ratio (OR (95% CI) 0.66 (0.55-0.80), p < 0.0001), transient ischaemic attack (0.52 (0.38-0.70), p < 0.0001), myocardial infarction (0.55 (0.41-0.75), p = 0.0002) and mortality (0.72 (0.56-0.94), p = 0.01) compared with general anaesthesia. Analysis of randomised controlled trials did not find a significant difference in the risk of stroke (0.92 (0.67-1.28), p = 0.63), transient ischaemic attack (2.20 (0.48-10.03), p = 0.31), myocardial infarction (1.25 (0.57-2.72), p = 0.58) or mortality (0.61 (0.35-1.05), p = 0.07) between local and general anaesthesia. On trial sequential analysis of the randomised trials, the Z-curve did not cross the α-spending boundaries or futility boundaries for stroke, mortality and transient ischaemic attack, suggesting that more trials are needed to reach conclusive results. Our meta-analysis of observational studies suggests that local anaesthesia for carotid endarterectomy may be associated with lower peri-operative morbidity and mortality compared with general anaesthesia. Although randomised studies have not confirmed any advantage for local anaesthesia, this may be due to a lack of pooled statistical power in these trials.

Oxidized Phospholipids on Apolipoprotein B-100 and Recurrent Ischemic Events Following Stroke or Transient Ischemic Attack.

BACKGROUND: Biomarkers to predict recurrent stroke and targets of therapy to prevent stroke are lacking. OBJECTIVES: This study evaluated whether patients with prior cerebrovascular events and elevated levels of oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), but without prior coronary artery disease (CAD), are at risk for recurrent stroke and CAD events following high-dose statin therapy. METHODS: In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, OxPL-apoB levels were measured in 4,385 patients with stroke or transient ischemic attack at baseline and in 3,106 patients at 5 years following randomization to placebo or 80 mg atorvastatin. The primary endpoint was the time from randomization to a second nonfatal or fatal stroke. Secondary endpoints included first major coronary events and any cardiovascular event. RESULTS: Patients with recurrent stroke had higher baseline median OxPL-apoB levels than patients without (15.5 nmol/l vs. 11.6 nmol/l; p < 0.0001). After multivariable adjustment, elevated baseline OxPL-apoB predicted recurrent stroke (hazard ratio [HR]: 4.3; p < 0.0001), first major coronary events (HR: 4.0; p < 0.0001), and any cardiovascular event (HR: 4.4; p < 0.0001). These comparisons for any endpoint did not differ by treatment, shown as a nonsignificant interaction test. The net reclassification improvement, integrated discrimination improvement, and area under the receiver-operating characteristic curve (AUC) were all significantly improved by adding OxPL-apoB to the models, with ΔAUC +0.0505 (p < 0.0001) for recurrent stroke, ΔAUC +0.0409 (p < 0.0001) for first major coronary event, and ΔAUC +0.0791 (p < 0.0001) for any cardiovascular event. CONCLUSIONS: Elevated OxPL-apoB levels predicted recurrent stroke and first major coronary events in patients with prior stroke or transient ischemic attack. The lack of statin-OxPL-apoB treatment interaction suggested that OxPLs might be statin-independent therapeutic targets to reduce risk of cardiovascular events. (Lipitor in the Prevention of Stroke, for Patients Who Have Had a Previous Stroke [SPARCL]; NCT00147602).

Hyperbaric oxygen and hyperbaric air preconditioning induces ischemic tolerance to transient forebrain ischemia in the gerbil.

Ischemic preconditioning with sublethal stress triggers defensive mechanisms against ischemic brain damage; however, such manipulations are potentially dangerous and, therefore, safe stimuli have been sought. Hyperoxia preconditioning by administration of hyperbaric (HBO) or normobaric oxygen (NBO) may have neuroprotective potential. The aim of this study was to determine whether preconditioning with HBO and air (HBA) applied at 2.5 absolute pressure (ATA) or NBO preconditioning induces ischemic tolerance in the brain of gerbils subjected to 3min transient cerebral ischemia. Neuronal cell survival, changes in brain temperature, the generation of factors involved in neurodegeneration and basic behavior in nest building were all tested. Hyperoxic preconditioning prevented ischemia-induced neuronal cell loss, reduced the number of TUNEL positive cells in the CA1 region of the hippocampus and improved the nest building process compared to untreated ischemic animals. Preconditioning also suppressed the production of reactive oxygen species and increased Bax expression normally observed after an ischemic episode. Only HBO preconditioning inhibited ischemia-evoked increases in brain temperature. Our results show that hyperoxic preconditioning results in induction of ischemic tolerance and prevents ischemia-induced neuronal damage in the gerbil brain. Pressurized air preconditioning was as effective as HBO or NBO preconditioning in providing neuroprotection. The observed neuroprotection probably results from mild oxidative stress evoked by increased brain tissue oxidation and activation of antioxidant and antiapoptotic defenses.

Long-Term Population-Based Cerebral Ischemic Event and Cognitive Outcomes of Direct Oral Anticoagulants Compared With Warfarin Among Long-term Anticoagulated Patients for Atrial Fibrillation.

Direct oral anticoagulants (DOACs) have been used in clinical practice in the United States for the last 4 to 6 years. Although DOACs may be an attractive alternative to warfarin in many patients, long-term outcomes of use of these medications are unknown. We performed a propensity-matched analysis to report patient important outcomes of death, stroke/transient ischemic attack (TIA), bleeding, major bleeding, and dementia in patients taking a DOAC or warfarin. Patients receiving long-term anticoagulation from June 2010 to December 2014 for thromboembolism prevention with either warfarin or a DOAC were matched 1:1 by index date and propensity score. Multivariable Cox hazard regression was performed to determine the risk of death, stroke/TIA, major bleed, and dementia by the anticoagulant therapy received. A total of 5,254 patients were studied (2,627 per group). Average age was 72.4 ± 10.9 years, and 59.0% were men. Most patients were receiving long-term anticoagulation for AF management (warfarin: 96.5% vs DOAC: 92.7%, p <0.0001). Rivaroxaban (55.3%) was the most commonly used DOAC, followed by apixaban (22.5%) and dabigatran (22.2%). The use of DOACs compared with warfarin was associated with a reduced risk of long-term adverse outcomes: death (p = 0.09), stroke/TIA (p <0.0001), major bleed (p <0.0001), and bleed (p = 0.14). No significant outcome variance was noted in DOAC-type comparison. In the AF multivariable model patients taking DOAC were 43% less likely to develop stroke/TIA/dementia (hazard ratio 0.57 [CI 0.17, 1.97], p = 0.38) than those taking warfarin. Our community-based results suggest better long-term efficacy and safety of DOACs compared with warfarin. DOAC use was associated with a lower risk of cerebral ischemic events and new-onset dementia.

Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants Compared With Uninterrupted Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation.

Anticoagulation in catheter ablation (CA) of atrial fibrillation (AF) is of paramount importance for prevention of thromboembolic events, and recent studies favor uninterrupted vitamin K antagonists (VKAs). We aimed to compare the efficacy and safety of new oral anticoagulants (NOACs) to uninterrupted VKAs for anticoagulation in CA by performing a meta-analysis. PubMed, EMBASE, the Cochrane Library, and Clinicaltrials.gov databases were searched for studies comparing NOACs with uninterrupted VKAs in patients who underwent CA for AF from January 1, 2000, to August 31, 2015. Odds ratio (OR) and Peto's OR (POR) were used to report for event rates >1% and <1%, respectively. A total of 11,686 patients with AF who underwent CA in 25 studies were included in this analysis. There was no significant difference between NOACs and uninterrupted VKAs in occurrence of stroke or transient ischemic attacks (POR 1.35, 95% CI 0.62 to 2.94) and major bleeding (POR 0.87, 95% CI 0.58 to 1.31), which were consistent in subgroup analysis of interrupted and uninterrupted NOACs. A lower risk of minor bleeding was observed with NOACs (OR 0.80, 95% CI 0.65 to 1.00), and no major differences were observed for the risk of thromboembolic events, cardiac tamponade or pericardial effusion requiring drainage, and groin hematoma. NOACs, whether interrupted preprocedure or not, were associated with equal rates of stroke or TIA and major bleeding complications and less risk of minor bleeding compared with uninterrupted VKAs in CA for AF.

Effectiveness and safety of rivaroxaban therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry.

The effectiveness and safety of rivaroxaban for stroke prevention in atrial fibrillation (SPAF) demonstrated in ROCKET AF needs to be confirmed in daily care. To evaluate effectiveness and safety of rivaroxaban therapy in SPAF patients in daily care, we used data from an ongoing, prospective, non-interventional registry of more than 2700 patients on novel oral anticoagulants in daily care. Between October 1, 2011 and February 28, 2013, a total of 1204 SPAF patients receiving rivaroxaban were enrolled. During a mean follow-up of 796.2 ± 207.3 days, the combined endpoint of stroke/transient ischaemic attack/systemic embolism occurred at a rate of 2.03/100 patient-years in the intention-to-treat analysis (95 % confidence interval [CI] 1.5-2.7) and at 1.7/100 patient-years in the on-treatment analysis (events within 3 days after last intake). On-treatment rates were higher in patients selected for 15 mg rivaroxaban (n=384) once daily [OD] compared with the 820 patients selected for 20 mg OD (2.7 [95 % CI 1.6-4.2] vs 1.25/100 patient-years [95 % CI 0.8-1.9]). On treatment, major bleeding occurred at a rate of 3.0/100 patient-years and significantly more often in patients receiving the 15 mg OD dose compared with the 20 mg OD dose (4.5 vs 2.4/100 patient-years). Rivaroxaban treatment discontinuation occurred in a total of 277 patients during follow-up (12.0/100 patient-years in Kaplan-Meier analysis). Our data contribute to the confirmation of effectiveness and relative safety of rivaroxaban in daily-care patients. Furthermore, rivaroxaban discontinuation rates were considerably lower than those reported for vitamin K antagonists.

Oenanthe Javanica Extract Protects Against Experimentally Induced Ischemic Neuronal Damage via its Antioxidant Effects.

BACKGROUND: Water dropwort (Oenanthe javanica) as a popular traditional medicine in Asia shows various biological properties including antioxidant activity. In this study, we firstly examined the neuroprotective effect of Oenanthe javanica extract (OJE) in the hippocampal cornus ammonis 1 region (CA1 region) of the gerbil subjected to transient cerebral ischemia. METHODS: Gerbils were established by the occlusion of common carotid arteries for 5 min. The neuroprotective effect of OJE was estimated by cresyl violet staining. In addition, 4 antioxidants (copper, zinc superoxide dismutase [SOD], manganese SOD, catalase, and glutathione peroxidase) immunoreactivities were investigated by immunohistochemistry. RESULTS: Pyramidal neurons in the CA1 region showed neuronal death at 5 days postischemia; at this point in time, all antioxidants immunoreactivities disappeared in CA1 pyramidal neurons and showed in many nonpyramidal cells. Treatment with 200 mg/kg, not 100 mg/kg, OJE protected CA1 pyramidal neurons from ischemic damage. In addition, 200 mg/kg OJE treatment increased or maintained antioxidants immunoreactivities. Especially, among the antioxidants, glutathione peroxidase immunoreactivity was effectively increased in the CA1 pyramidal neurons of the OJE-treated sham-operated and ischemia-operated groups. CONCLUSION: Our present results indicate that treatment with OJE can protect neurons from transient ischemic damage and that the neuroprotective effect may be closely associated with increased or maintained intracellular antioxidant enzymes by OJE.

Treatment of Rivaroxaban versus Aspirin for Non-disabling Cerebrovascular Events (TRACE): study protocol for a randomized controlled trial.

BACKGROUND: Transient ischemic attack (TIA) or minor ischemic stroke represents the largest group of cerebrovascular disease, and those patients have a high risk of early recurrent stroke. Over decades, anticoagulation therapy has been used prudently in them for likely increasing the risk of intra-/extra-cranial hemorrhagic complications. However, recently rivaroxaban, a new oral anticoagulant, is proved to be as effective as traditional anticoagulants, while carrying significantly less risk of intracranial hemorrhage. Therefore, we assumed that patients may benefit from rivaroxaban if treated soon after TIA or minor stroke, and designed this adequately powered randomized study, TRACE. METHODS AND DESIGN: The Treatment of Rivaroxaban versus Aspirin in Non-disabling Cerebrovascular Events (TRACE) study is a randomized, double-blind clinical trial with a target enrollment of 4400 patients. A 14-days regimen of rivaroxaban 10 mg daily or a 14-days regimen of aspirin 100 mg daily will be administrated to randomized participants with acute TIA or minor stroke, defined as National Institute of Health Stroke Scale scores ≤ 3. The primary efficacy end point is percentage of patients with any stroke (ischemic or hemorrhage) at 14 days. Study visits will be performed at the day of randomization, day 14 and day 90. DISCUSSION: Even though the new oral anticoagulants seem to be both safe and effective, few clinical trials have been carried out to test their effect on non-disabling cerebrovascular events. Treatment with rivaroxaban may prevent more cerebrovascular events with an acceptable risk profile after TIA or minor stroke, compared with aspirin, thus helping to improve the outcome of the disease. TRIAL REGISTRATION: No. NCT01923818.

Use of secondary stroke prevention medicines in Australia: national trends, 2003-2009.

OBJECTIVE: To examine recent trends in the use of secondary stroke prevention medicines by transient ischaemic attack (TIA) and ischaemic stroke survivors. DESIGN, SETTING AND PARTICIPANTS: Retrospective observational study of patients aged ≥ 65 years who were hospitalised with a TIA or ischaemic stroke between January 2000 and December 2009. Use of antihypertensive, antithrombotic and lipid-lowering medicines by patients was determined monthly, using claims data from the Australian Government Department of Veterans' Affairs, commencing in January 2003. MAIN OUTCOME MEASURE: Monthly prevalence of use of secondary stroke prevention medicines. RESULTS: Between 2003 and 2009, small increases in use (less than 2% relative increase annually) were observed for antihypertensive and antithrombotic medicines among 19 019 patients. There was a 9% relative increase in use of lipid-lowering therapy each year. The proportion of patients dispensed all three recommended medicine classes nearly doubled over the 7-year period. By December 2009, about 80% of patients were dispensed an antihypertensive, 75% received an antithrombotic and 60% were dispensed lipid-lowering therapy. Almost half of the population were dispensed all three recommended classes by the end of the study period. CONCLUSIONS: Increased use of secondary stroke prevention medicines was shown in this study, in accordance with national stroke guideline recommendations and initiatives supporting quality use of medicines in Australia. There may be opportunity to further increase use of these medicines among older Australians who have had a TIA or ischaemic stroke.

Total bakkenolides protects neurons against cerebral ischemic injury through inhibition of nuclear factor-κB activation.

Total bakkenolides is the major component of the rhizome of Petasites trichinous Franch.. In this study, we investigated its neuroprotective effects in a rat transient focal cerebral ischemia-reperfusion model, and in an in vitro cerebral ischemia model, oxygen-glucose deprivation of cultured nerve cells. Oral administration of total bakkenolides immediately after reperfusion at doses of 5, 10 and 20 mg/kg markedly reduced brain infarct volume and neurological deficits. Total bakkenolides significantly attenuated cell death and apoptosis in primarily cultured neurons subject to 1-h hypoxia followed by 24-h reoxygenation. Morphologic observations directly confirmed its protective effect on neurons. We also demonstrated that total bakkenolides could inhibit nuclear factor-κB (NF-κB) activation by blocking the classic activation pathway through suppression of phosphorylation of IκB-kinase complex, NF-κB/p65 and inhibitor protein IκB, inducing nuclear translocation of NF-κB/p65 and degradation of IκB. Further, total bakkenolides inhibited the activation of Akt and the extracellular signal-regulated kinase 1/2, two important upstream activators of NF-κB. In conclusion, our results provide a strong pharmacological basis for further understanding the potential therapeutic role of total bakkenolides in cerebral ischemic disease and shed new light on its neuroprotective mechanism.

Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du-Decotion (HLJDD, Hwangryun-Hae-Dok-Decotion in Japan), an ancient antipyretic and detoxifying traditional Chinese medicine formula, was reported to have protective effect on ischemic stroke. AIM OF THE RESEARCH: To investigate the therapeutic effect of HLJDD on ischemic stroke and explore its mode of action. MATERIAL AND METHODS: A model of ischemic stroke in the rat was established after transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Rats were assigned randomly to groups of control, sham, transient ischemia/reperfusion (I/R), and three treatment groups by HLJDD at 2.5, 5.0, 10.0mg/kg. The neurological deficit, the cerebral infarct size, morphology abnormality, biochemical parameters were examined, and the levels of relevant proteins were determined by immunoblotting analysis to evaluate the protective effects of HLJDD on ischemic stroke and explore the underlying mechanism. RESULTS: Compared with I/R group, HLJDD significantly ameliorated neurological deficit and histopathology changes, decreased infarct area, and restored the levels of biochemical indicators including nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), total superoxide dismutase (T-SOD), Cu/Zn-SOD, Mn-SOD and glutathione peroxidase (GSH-PX). HLJDD also notably elevated the levels of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and other autophagy related genes (Atgs), promoted the activation of extracellular signal-regulated kinases (ERK), protein kinase B (Akt), 3-phosphoinositide-dependent kinase (PDK1), and inhibited the activation of mammalian target of rapamycin (mTOR), c-Jun N-terminal protein kinases (JNK), p38, phosphatase and tensin homolog (PTEN). CONCLUSION: HLJDD showed neuroprotective effects on ischemic stroke, at least in part to the induced protective autophagy via the regulation of mitogen-activated protein kinase (MAPK) signals. This Akt-independent protective autophagy is favorable in the treatment of stroke, avoiding unfavorable side-effects associated with the inactivation of Akt. The efficacy of HLJDD on ischemic stroke and its safety warranted by its long-term clinical use in traditional Chinese medicine favored further study to develop HLJDD as an effective therapeutic agent to treat ischemic stroke.