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The Benefits and Risks of Statin Therapy in Ischemic Stroke: A Review of the Literature.
Zhao, W, Xiao, ZJ, Zhao, SP
Neurology India. 2019;(4):983-992
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Statins are effective cholesterol-lowering drugs for reducing the risks of mortality and morbidity of cardiovascular diseases. Increasing evidence has shown that statin use is associated with a significant beneficial effect in patients with ischemic stroke. Both pre-stroke and post-stroke statin use has been found to be beneficial in ischemic stroke. Furthermore, good adherence is associated with a better clinical outcome, and statin withdrawal is associated with a poor functional outcome in patients with ischemic stroke. High-intensity statin therapy is advocated for the treatment of ischemic stroke. However, there are concerns regarding the adverse effects associated with statin use in ischemic stroke such as intracranial hemorrhage. In this review, we summarize the beneficial effect of statin use in ischemic stroke and discuss the potential risks associated with statin therapy.
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Intravenous tPA (Tissue-Type Plasminogen Activator) in Patients With Acute Ischemic Stroke Taking Non-Vitamin K Antagonist Oral Anticoagulants Preceding Stroke.
Jin, C, Huang, RJ, Peterson, ED, Laskowitz, DT, Hernandez, AF, Federspiel, JJ, Schwamm, LH, Bhatt, DL, Smith, EE, Fonarow, GC, et al
Stroke. 2018;(9):2237-2240
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Background and Purpose- Although there are no trials or large cohorts to inform clinical care, current guidelines caution against giving intravenous tPA (tissue-type plasminogen activator) to patients with acute ischemic stroke who are taking non-vitamin K antagonist oral anticoagulants (NOACs). We performed a literature review of intravenous tPA in patients treated with NOACs preceding stroke. Methods- A literature search of PubMed was performed encompassing January 2010 to March 2018. Patient characteristics, timing of last medication intake, laboratory testing, use of reversal, and outcomes ≤3 months after discharge were summarized. Results- We identified 55 studies with 492 NOAC patients receiving tPA (dabigatran, 181; rivaroxaban, 215; apixaban, 40; and unspecified NOAC, 56). Among patients with complete data, the median time from the last NOAC intake to symptom onset was 8 hours (interquartile range, 2.5-14.5), with 55.2% (80/145) within 12 hours. Few patients underwent sensitive laboratory tests, such as thrombin time, diluted thrombin time, or anti-Xa assays before tPA administration. The overall observed rates of symptomatic intracranial hemorrhage, mortality, and favorable outcomes (National Institutes of Health Stroke Scale score, ≤1; modified Rankin Scale score, 0-2; or neurological improvement in the National Institutes of Health Stroke Scale score, ≥8 points) were 4.3% (20/462), 11.3% (48/423), and 43.7% (164/375), respectively. Among dabigatran-treated patients, reversal with idarucizumab was associated with fewer symptomatic intracranial hemorrhage (4.5% [2/44] versus 7.4% [8/108]; unadjusted odds ratio, 0.60; 95% CI, 0.12-2.92), death (4.5% [2/44] versus 12.0% [13/108]; unadjusted odds ratio, 0.35; 95% CI, 0.08-1.61), and more favorable outcomes (79.1% [34/43] versus 39.2% [29/74]; unadjusted odds ratio, 5.86; 95% CI, 2.45-14.00), although the differences were not statistically significant for symptomatic intracranial hemorrhage and death. Conclusions- These preliminary observations suggest that tPA may be reasonably well tolerated without prohibitive risks of bleeding complications in selected patients on NOACs. Reversal of anticoagulant effects by idarucizumab for dabigatran-treated patients before tPA is an emerging strategy that was associated with more favorable outcomes.
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Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation.
Korompoki, E, Filippidis, FT, Nielsen, PB, Del Giudice, A, Lip, GYH, Kuramatsu, JB, Huttner, HB, Fang, J, Schulman, S, Martí-Fàbregas, J, et al
Neurology. 2017;(7):687-696
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OBJECTIVE To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up. METHODS A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for ≥3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method. RESULTS Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27-0.74, p = 0.002) and no-ATM (RR = 0.47, 95% CI 0.29-0.77, p = 0.002). Pooled RR estimates for ICH recurrence were not significantly increased across treatment groups (VKA vs APA: RR = 1.34, 95% CI 0.79-2.30, p = 0.28; VKA vs no-ATM: RR = 0.93, 95% CI 0.45-1.90, p = 0.84). CONCLUSIONS In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF.
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Risk factor management for stroke prevention.
Prabhakaran, S, Chong, JY
Continuum (Minneapolis, Minn.). 2014;(2 Cerebrovascular Disease):296-308
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PURPOSE OF REVIEW This review focuses on the recommendations for management of hypertension, dyslipidemia, diabetes mellitus, diet, physical activity, and lifestyle choices commonly encountered in neurologic practice. Specific studies, including those relevant to lipid targets, blood pressure targets, and adherence to medications after stroke, are reviewed. RECENT FINDINGS In addition to traditional risk factors such as hypertension, dyslipidemia, and diabetes mellitus, this review discusses sleep apnea, diet, physical activity, and other novel risk factors that are potentially modifiable. Recent studies confirm that pharmacologic strategies to achieve aggressive targets for lipid and blood pressure lowering have significant impact on recurrent stroke risk. SUMMARY Optimal secondary prevention strategies can prevent as much as 80% of all recurrent strokes.
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Molecular targets underlying SUMO-mediated neuroprotection in brain ischemia.
Silveirinha, V, Stephens, GJ, Cimarosti, H
Journal of neurochemistry. 2013;(5):580-91
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SUMOylation (small ubiquitin-like modifier conjugation) is an important post-translational modification which is becoming increasingly implicated in the altered protein dynamics associated with brain ischemia. The function of SUMOylation in cells undergoing ischemic stress and the identity of small ubiquitin-like modifier (SUMO) targets remain in most cases unknown. However, the emerging consensus is that SUMOylation of certain proteins might be part of an endogenous neuroprotective response. This review brings together the current understanding of the underlying mechanisms and downstream effects of SUMOylation in brain ischemia, including processes such as autophagy, mitophagy and oxidative stress. We focus on recent advances and controversies regarding key central nervous system proteins, including those associated with the nucleus, cytoplasm and plasma membrane, such as glucose transporters (GLUT1, GLUT4), excitatory amino acid transporter 2 glutamate transporters, K+ channels (K2P1, Kv1.5, Kv2.1), GluK2 kainate receptors, mGluR8 glutamate receptors and CB1 cannabinoid receptors, which are reported to be SUMO-modified. A discussion of the roles of these molecular targets for SUMOylation could play following an ischemic event, particularly with respect to their potential neuroprotective impact in brain ischemia, is proposed.
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Zinc: new clues to diverse roles in brain ischemia.
Shuttleworth, CW, Weiss, JH
Trends in pharmacological sciences. 2011;(8):480-6
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Cerebral ischemia is a leading cause of morbidity and mortality, reflecting the extraordinary sensitivity of the brain to a brief loss of blood flow. A significant goal has been to identify pathways of neuronal injury that are selectively activated after stroke and may be amenable to drug therapy. An important advance was made nearly 25 years ago when Ca(2+) overload was implicated as a critical link between glutamate excitotoxicity and ischemic neurodegeneration. However, early hope for effective therapies faded as glutamate-targeted trials repeatedly failed to demonstrate efficacy in humans. In a review in 2000 in this journal, we described new evidence linking a related cation, zinc (Zn(2+)), to neuronal injury, emphasizing sources and mechanisms of Zn(2+) toxicity. The current review highlights progress over the last decade, emphasizing mechanisms through which Zn(2+) ions (from multiple sources) participate together with Ca(2+) in different stages of cascades of ischemic injury.
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Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials.
Schürks, M, Glynn, RJ, Rist, PM, Tzourio, C, Kurth, T
BMJ (Clinical research ed.). 2010;:c5702
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OBJECTIVE To evaluate the effect of vitamin E supplementation on incident total, ischaemic, and haemorrhagic stroke. DESIGN Systematic review and meta-analysis of randomised, placebo controlled trials published until January 2010. DATA SOURCES Electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials) and reference lists of trial reports. Selection criteria Randomised, placebo controlled trials with ≥1 year of follow-up investigating the effect of vitamin E on stroke. Review methods and data extraction Two investigators independently assessed eligibility of identified trials. Disagreements were resolved by consensus. Two different investigators independently extracted data. Risk ratios (and 95% confidence intervals) were calculated for each trial based on the number of cases and non-cases randomised to vitamin E or placebo. Pooled effect estimates were then calculated. RESULTS Nine trials investigating the effect of vitamin E on incident stroke were included, totalling 118 765 participants (59 357 randomised to vitamin E and 59 408 to placebo). Among those, seven trials reported data for total stroke and five trials each for haemorrhagic and ischaemic stroke. Vitamin E had no effect on the risk for total stroke (pooled relative risk 0.98 (95% confidence interval 0.91 to 1.05), P=0.53). In contrast, the risk for haemorrhagic stroke was increased (pooled relative risk 1.22 (1.00 to 1.48), P=0.045), while the risk of ischaemic stroke was reduced (pooled relative risk 0.90 (0.82 to 0.99), P=0.02). There was little evidence for heterogeneity among studies. Meta-regression did not identify blinding strategy, vitamin E dose, or morbidity status of participants as sources of heterogeneity. In terms of absolute risk, this translates into one additional haemorrhagic stroke for every 1250 individuals taking vitamin E, in contrast to one ischaemic stroke prevented per 476 individuals taking vitamin E. CONCLUSION In this meta-analysis, vitamin E increased the risk for haemorrhagic stroke by 22% and reduced the risk of ischaemic stroke by 10%. This differential risk pattern is obscured when looking at total stroke. Given the relatively small risk reduction of ischaemic stroke and the generally more severe outcome of haemorrhagic stroke, indiscriminate widespread use of vitamin E should be cautioned against.
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Ca2+ signals and death programmes in neurons.
Berliocchi, L, Bano, D, Nicotera, P
Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2005;(1464):2255-8
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Cell death programmes are generally defined by biochemical/genetic routines that are linked to their execution and by the appearance of more or less typical morphological features. However, in pathological settings death signals may engage complex and interacting lethal pathways, some of which are common to different cells, whereas others are linked to a specific tissue and differentiation pattern. In neurons, death programmes can be spatially and temporally segregated. Most importantly physiological Ca2+ signals are essential for cell function and survival. On the other hand, Ca2+ overload or perturbations of intracellular Ca2+ compartmentalization can activate or enhance mechanisms leading to cell death. An imbalance between Ca2+ influx and efflux from cells is the initial signal leading to Ca2+ overload and death of ischaemic neurons or cardiomyocytes. Alterations of intracellular Ca2+ storage can integrate with death signals that do not initially require Ca2+, to promote processing of cellular components and death by apoptosis or necrosis. Finally, Ca2+ can directly activate catabolic enzymes such as proteases, phospholipases and nucleases that directly cause cell demise and tissue damage.