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• W2042615907 abstract "HomeStrokeVol. 42, No. 2Advances in Emerging Therapies 2010 Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessResearch ArticlePDF/EPUBAdvances in Emerging Therapies 2010 Heinrich P. Mattle, MD and Sean I. Savitz, MD Heinrich P. MattleHeinrich P. Mattle From the Department of Neurology (H.P.M.), Inselspital, University of Bern, Bern, Switzerland; and the Department of Neurology (S.I.S.), UT-Health, The University of Texas Medical School, Houston, TX. Search for more papers by this author and Sean I. SavitzSean I. Savitz From the Department of Neurology (H.P.M.), Inselspital, University of Bern, Bern, Switzerland; and the Department of Neurology (S.I.S.), UT-Health, The University of Texas Medical School, Houston, TX. Search for more papers by this author Originally published13 Jan 2011https://doi.org/10.1161/STROKEAHA.110.605071Stroke. 2011;42:298–300Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 In 2010, there were significant advancements in stroke prevention, whereas there were fewer studies that unearthed new ground on treatment of acute stroke and rehabilitation. We first discuss important pivotal studies in stroke prevention followed by acute treatment and rehabilitation.PreventionHomocysteine, Folic Acid, and B VitaminsApproximately 90% of all strokes are attributable to vascular risk factors.1 Homocysteine has also been identified as another risk factor for stroke. VITAmins TO Prevent Stroke (VITATOPS) aimed to assess whether daily administration of folic acid, vitamin B6, and vitamin B12 in patients with recent stroke or transient ischemic attack lowers homocysteine and reduces major vascular events. The data overall and pooled analysis of individual patient data showed that B vitamins have no or at most a marginal positive effect on reducing vascular events.2Blood PressureThere is a correlation between blood pressure levels and risk of stroke. Data from Rothwell and colleagues now show that not only blood pressure levels, but also blood pressure variability account for stroke risk. A meta-analysis of antihypertensive drug trials found that calcium channel blockers and nonloop diuretic drugs were more effective than other antihypertensive agents to reduce blood pressure variability.3 Drug-class effects on interindividual variation in blood pressure can explain differences in effects of antihypertensive drugs on risk of stroke independently of their effects on mean systolic blood pressure. This means that the ideal antihypertensive agent should lower both blood pressure levels and variation in blood pressure to reduce stroke risk; however, we currently do not have such agents in our pharmacopeia for stroke prevention.Antithrombotic Drugs and Cerebrovascular DiseasesNew data have emerged on some age old questions about carotid dissection and intracranial stenosis. The use of aspirin or anticoagulation in spontaneous carotid artery dissection is a matter of debate with little data to guide decision-making. Data within a nonrandomized study suggest that the frequency of new cerebral and retinal ischemic events in patients with carotid dissection was low and probably independent of the type of antithrombotic treatment.4 In patients with predominantly intracranial symptomatic atherosclerotic stenosis, a short-term combination therapy with clopidogrel and aspirin was more effective than aspirin alone in reducing microembolic signals, and a combined analysis with data from the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis (CARESS) study also showed a clinical benefit.5 This study and CARESS demonstrate that short-term dual antiplatelet therapy with clopidogrel and aspirin may be superior to monotherapy in reducing stroke in patients with symptomatic stenosis of the cerebral arteries.Anticoagulation with warfarin has been the treatment of choice for stroke prevention in patients with atrial fibrillation. A long-awaited alternative is now available. Dabigatran is a direct thrombin inhibitor and has recently been approved by the Food and Drug Administration for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation based on the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study.6 Depending on the dose, dabigatran has proved to be equal or superior than warfarin to prevent emboli but with lower or equal rates of major hemorrhages. In addition, the Rivaroxaban—Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study has also compared rivaroxaban, a factor Xa inhibitor, with warfarin in patients with atrial fibrillation. Rivaroxaban was noninferior for the prevention of stroke and noncentral nervous system embolism and may also potentially become an alternative to warfarin for this indication as well.7Carotid Stenosis: Stenting and EndarterectomyIn Spring 2010 the International Carotid Stenting Study (ICSS), the third largest trial comparing carotid endarterectomy and stenting for treatment of symptomatic carotid stenosis, was published.8 Like in Endarterectomy Versus Angioplasty in patients with Symptomatic Severe carotid Stenosis (EVA-3S) and Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) Studies, endarterectomy was associated with less periprocedural complications and was better than stenting after short-term follow-up.9 Complication rates in patients <70 years were less compared with older patients, and the risk–benefit ratio might even favor stenting in younger patients. Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), the North American trial comparing stenting and endarterectomy, gave further support to stenting for both symptomatic and asymptomatic carotid stenosis.10 Periprocedural strokes, myocardial infarctions, and death occurred equally in both treatment arms. Strokes were somewhat more frequent with endovascular treatment, myocardial infarctions with surgery, and younger patients tended to fare better with stenting. After CREST, many physicians consider carotid stenting as an alternative to carotid surgery, especially in younger patients. However, the results support an argument against stenting and that the long-term outcome of stenting and the rate of recurrent symptomatic stenosis are not reliably known.With respect to carotid endarterectomy and asymptomatic stenosis, the Asymptomatic Carotid Atherosclerosis Study (ACAS) and Asymptomatic Carotid Stenosis Trial (ACST) trials have provided the best evidence that carotid endarterectomy for asymptomatic stenosis reduces stroke. Recently, the 10-year data of ACST have confirmed that successful carotid endarterectomy for asymptomatic patients <75 years reduces 10-year stroke risks.11 The net benefit will depend on the risks from unoperated carotid lesions, which has also changed in recent years because of improved medical management. Further studies comparing modern medical management and revascularization with adjunctive best medical therapy are needed.Intracranial Stenosis and StentingThe Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) study has shown a high risk of stroke in patients with high-grade symptomatic intracranial atherosclerotic stenosis. A German multicenter registry has confirmed a similarly high risk: 18% and 23% of patients had a stroke after 1 and 3 years with medical therapy.12 When stenting was used as an adjunct to medical therapy, 4.8% disabling strokes and 2.2% peri-interventional deaths occurred according to the German INTRASTENT multicentric registry.13 The numbers show that randomized trials to solve the issue of stenting of intracranial stenoses are needed.Acute Ischemic StrokeIntravenous ThrombolysisThe European Cooperative Acute Stroke Study (ECASS) III showed benefit of intravenous recombinant tissue plasminogen activator up to 4.5 hours after symptom onset and a decreasing benefit with elapsing time.14 A new analysis from the Virtual International Stroke Trials Archive (VISTA) collaborators has found that all patients benefit from recombinant tissue plasminogen activator, but areas of uncertainty include those patients with minor (National Institutes of Health Stroke Scale ≤4) or very severe strokes (National Institutes of Health Stroke Scale >25).15 A further analysis of the Safe Implementation of Thrombolysis in Stroke (SITS) registry has addressed the safety of recombinant tissue plasminogen activator for patients with stroke at the time of being on antiplatelet agents. Their excess risk of symptomatic intracranial bleedings was 1.4%, which is small compared with the benefit that has been observed in randomized trials.16Blood pressure is elevated in up to 80% of patients with acute stroke. Pathophysiological considerations and guidelines tell us not to manipulate blood pressure in the acute setting except when values are extremely high or low. The Continue or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS) study has partially addressed this question whether to stop or continue antihypertensive drugs in acute stroke. Seven hundred sixty-three patients with acute ischemic strokes were randomized to “stop antihypertensives” or “continue antihypertensives.”17 The blood pressure of the 2 groups did differ as expected, but not their clinical outcomes. COSSACS lends support to current recommendations to resume antihypertensive treatment soon after the acute phase of ischemic stroke.HyperglycemiaHyperglycemia in acute stroke is well known to be associated with a worse outcome. However, rapid lowering of glucose with insulin does not reduce infarct size and does not improve recovery of patients with acute stroke.18 This study raises serious doubts about lowering glucose as a therapy for acute stroke.Stent-Assisted Mechanical RecanalizationMultimodel recanalization techniques have been improved significantly in recent years combining bridging of intravenous recombinant tissue plasminogen activator and endovascular recanalization using drugs and mechanical devices. The most recent advance is self-expanding retrievable stents. They have been tested both in animals and humans and bring recanalization rates up to 90%.19,20 Whether such devices will improve the fate of patients with stroke will need to be tested in large registries or randomized trials.RecoveryIn a multicenter randomized controlled trial, 127 patients with moderate-to-severe upper-limb impairment ≥6 months after a stroke were randomly assigned to receive intensive robot-assisted therapy, intensive comparison therapy, or standard of care.21 Therapy consisted of 36 1-hour sessions over a period of 12 weeks. After 12 weeks, patients receiving robot-assisted therapy or intensive care showed nonsignificant improved motor functions. After 36 weeks, robot-assisted and intensive therapy had significantly improved motor function as compared with standard of care. Although considered a negative study on the primary outcome, which was based on a 12-week assessment, robot-assisted therapy improved motor capability and motor task performance over 36 weeks compared with usual care. More importantly, the study provides evidence of the potential long-term benefits of intensive rehabilitation in patients with moderate-to-severe impairment, even years after a stroke.DisclosuresH.P.M. has received speaking fees, consulting honoraria, or research support from AGA Medical, Amgen, Bayer, Boehringer-Ingelheim, Pfizer, Sanofi-Aventis, and Servier. S.I.S. attended an advisory meeting sponsored by Otsukara and received a speaking fee from Sanofi-Aventis.FootnotesCorrespondence to Heinrich P. Mattle, MD, Department of Neurology, Inselspital, 3010 Bern, Switzerland. E-mail heinrich.[email protected]ch.References1. INTERSTROKE investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case–control study. Lancet. 2010; 376:112–123.CrossrefMedlineGoogle Scholar2. VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol. 2010; 9:855–865.CrossrefMedlineGoogle Scholar3. Rothwell PM, Howard SC, Dolan E, O'Brien E, Dobson JE, Dahlöf B, Poulter NR, Sever PS; ASCOT-BPLA and MRC Trial Investigators. Effects of β-blockers and calcium-channel-blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol. 2010; 9:469–480.CrossrefMedlineGoogle Scholar4. Georgiadis D, Arnold M, von Buedingen HC, Valko P, Sarikaya H, Rousson V, Mattle HP, Bousser MG, Baumgartner RW. Aspirin vs anticoagulation in carotid artery dissection: a study of 298 patients. Neurology. 2009; 72:1810–1815.CrossrefMedlineGoogle Scholar5. CLAIR study investigators. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010; 9:489–497.CrossrefMedlineGoogle Scholar6. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361:1139–1151.CrossrefMedlineGoogle Scholar7. AF ROCKET Study. Presented at the AHA Meeting; Chicago, IL; November 15, 2010.Google Scholar8. International Carotid Stenting Study investigators. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet. 2010; 375:985–997.CrossrefMedlineGoogle Scholar9. Carotid Stenting Trialists' Collaboration. Short-term outcome after stenting versus endarterectomy for symptomatic carotid stenosis: a preplanned meta-analysis of individual patient data. Lancet. 2010; 376:1062–1073.CrossrefMedlineGoogle Scholar10. CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010; 363:11–23.CrossrefMedlineGoogle Scholar11. Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet. 2010; 376:1074–1084.CrossrefMedlineGoogle Scholar12. Weber R, Kraywinkel K, Diener HC, Weimar C; German Stroke Study Collaboration. Symptomatic intracranial atherosclerotic stenoses: prevalence and prognosis in patients with acute cerebral ischemia. Cerebrovasc Dis. 2010; 30:188–193.CrossrefMedlineGoogle Scholar13. Kurre W, Berkefeld J, Brassel F, Brüning R, Eckert B, Kamek S, Klein GE, Knauth M, Liebig T, Maskova J, Mucha D, Neumann-Haefelin T, Pilgram-Pastor S, Sitzer M, Sonnberger M, Tietke M, Trenkler J, Turowski Bfor the INTRASTENT Study Group. In-hospital complication rates after stent treatment of 388 symptomatic intracranial stenoses—results From the INTRASTENT Mutlicentric Registry. Stroke. 2010; 41:494–498.LinkGoogle Scholar14. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke WECASS, ATLANTIS, NINDS and EPITHET rt-PA Study Group, Allen K, Mau J, Meier D, del Zoppo G, De Silva DA, Butcher KS, Parsons MW, Barber PA, Levi C, Bladin C, Byrnes G. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010; 375:1695–1703.CrossrefMedlineGoogle Scholar15. Mishra NK, Lyden P, Grotta JC, Lees KR; for the VISTA Collaborators. Thrombolysis is associated with consistent functional improvement across baseline stroke severity. a comparison of outcomes in patients from the Virtual International Stroke Trials Archive (VISTA). Stroke. 2010; 41:2612–2617.LinkGoogle Scholar16. Diedler J, Ahmed N, Sykora M, Uyttenboogaart M, Overgaard K, Luijckx GJ, Soinne L, Ford GA, Lees KR, Wahlgren N, Ringleb P. Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset. Stroke. 2010; 41:288–294.LinkGoogle Scholar17. Robinson TG, Potter JF, Ford GA, Bulpitt CJ, Chernova J, Jagger C, James MA, Knight J, Markus HS, Mistri AK, Poulter NR; COSSACS Investigators. Effects of antihypertensive treatment after acute stroke in the Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomised, open, blinded-endpoint trial. Lancet Neurol. 2010; 9:767–775.CrossrefMedlineGoogle Scholar18. McCormick M, Hadley D, McLean JR, Macfarlane JA, Condon B, Muir KW. Randomized, controlled trial of insulin for acute poststroke hyperglycemia. Ann Neurol. 2010; 67:570–578.MedlineGoogle Scholar19. Mordasini P, Frabetti N, Gralla J, Schroth G, Fischer U, Arnold M, Brekenfeld C. In vivo evaluation of the first dedicated combined flow-restoration and mechanical thrombectomy device in a swine model of acute vessel occlusion. AJNR Am J Neuroradiol. 2010Oct 21 [Epub ahead of print].CrossrefGoogle Scholar20. Castaño C, Dorado L, Guerrero C, Millán M, Gomis M, Perez de la Ossa N, Castellanos M, García MR, Domenech S, Dávalos A. Mechanical thrombectomy with the Solitaire AB device in large artery occlusions of the anterior circulation: a pilot study. Stroke. 2010; 41:1836–1840.LinkGoogle Scholar21. Lo AC, Guarino PD, Richards LG, Haselkorn JK, Wittenberg GF, Federman DG, Ringer RJ, Wagner TH, Krebs HI, Volpe BT, Bever CT, Bravata DM, Duncan PW, Corn BH, Maffucci AD, Nadeau SE, Conroy SS, Powell JM, Huang GD, Peduzzi P. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med. 2010; 362:1772–1783.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ekusheva E and Damulin I (2015) Post-Stroke Rehabilitation: Importance of Neuroplasticity and Sensorimotor Integration Processes, Neuroscience and Behavioral Physiology, 10.1007/s11055-015-0117-5, 45:5, (594-599), Online publication date: 1-Jun-2015. Mir O and Savitz S (2015) Just Over the Horizon: Catheter Delivery of Stem Cell Therapy Neurointervention in the Medical Specialties, 10.1007/978-1-4939-1942-0_19, (343-350), . Mir O, Lal A, Vahidy F, Parsha K and Savitz S (2013) Intravenous Cell Therapies for Stroke Cell-Based Therapies in Stroke, 10.1007/978-3-7091-1175-8_12, (171-179), . Mir O and Savitz S (2014) Stem cell therapy in stroke treatment: is it a viable option?, Expert Review of Neurotherapeutics, 10.1586/ern.12.164, 13:2, (119-121), Online publication date: 1-Feb-2013. February 2011Vol 42, Issue 2 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.110.605071PMID: 21233471 Manuscript receivedNovember 29, 2010Manuscript acceptedDecember 7, 2010Originally publishedJanuary 13, 2011 Keywordsacute stroke treatmentstroke preventionPDF download Advertisement SubjectsAnticoagulantsCerebrovascular ProceduresPercutaneous Coronary InterventionTreatment" @default.
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