Diabetes Mellitus, Admission Glucose, and Outcomes After Stroke Thrombolysis: A Registry and Systematic Review

Background and Purpose— The potential detrimental effect of diabetes mellitus and admission glucose level (AGL) on outcomes after stroke thrombolysis is unclear. We evaluated outcomes of patients treated by intravenous and/or intra-arterial therapy, according to diabetes mellitus and AGL. Methods— We analyzed data from a patient registry (n=704) and conducted a systematic review of previous observational studies. The primary study outcome was the percentage of patients who achieved a favorable outcome (modified Rankin score ⩽2 at 3 months). Results— We identified 54 previous reports that evaluated the effect of diabetes mellitus or AGL on outcomes after thrombolysis. In an unadjusted meta-analysis that included our registry data and previous available observational data, diabetes mellitus was associated with less favorable outcome (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.73–0.79) and more symptomatic intracranial hemorrhage (OR, 1.38; 95% CI, 1.21–1.56). However, in multivariable analysis, diabetes mellitus remained associated with less favorable outcome (OR, 0.77; 95% CI, 0.69–0.87) but not with symptomatic intracranial hemorrhage (OR, 1.11; 95% CI, 0.83–1.48). In unadjusted and in adjusted meta-analysis, higher AGL was associated with less favorable outcome and more symptomatic intracranial hemorrhage; the adjusted OR (95% CI) per 1 mmol/L increase in AGL was 0.92 (0.90–0.94) for favorable outcome, and 1.09 (1.04–1.14) for symptomatic intracranial hemorrhage. Conclusions— These results confirm that AGL and history of diabetes mellitus are associated with poor clinical outcome after thrombolysis. AGL may be a surrogate marker of brain infarction severity rather than a causal factor. However, randomized controlled evidences are needed to address the significance of a tight glucose control during thrombolysis on clinical outcome.

[1]  G. Pellegrini,et al.  Acute hyperglycemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat , 2001, Acta Diabetologica.

[2]  Eric E. Smith,et al.  Management of thrombolysis-associated symptomatic intracerebral hemorrhage. , 2010, Archives of neurology.

[3]  C. Molina,et al.  Tandem Internal Carotid Artery/Middle Cerebral Artery Occlusion: An Independent Predictor of Poor Outcome After Systemic Thrombolysis , 2006, Stroke.

[4]  K. Kario,et al.  Routine Use of Intravenous Low-Dose Recombinant Tissue Plasminogen Activator in Japanese Patients: General Outcomes and Prognostic Factors From the SAMURAI Register , 2009, Stroke.

[5]  H. Gerstein,et al.  Stress Hyperglycemia and Prognosis of Stroke in Nondiabetic and Diabetic Patients: A Systematic Overview , 2001, Stroke.

[6]  D. Salat,et al.  Ischemic Stroke Outcome and Early Infection: Its Deleterious Effect Seems to Operate Also among Tissue Plasminogen Activator-Treated Patients , 2011, European Neurology.

[7]  P. Heuschmann,et al.  Predictors of in-hospital mortality in patients with acute ischemic stroke treated with thrombolytic therapy , 2004 .

[8]  F. Dubas Pathologie des petites arteres et hémorragies cérébrales , 2003 .

[9]  A. Alexandrov,et al.  Pre–Tissue Plasminogen Activator Blood Pressure Levels and Risk of Symptomatic Intracerebral Hemorrhage , 2009, Stroke.

[10]  R. Swanson,et al.  Glucose and NADPH oxidase drive neuronal superoxide formation in stroke , 2008, Annals of neurology.

[11]  R. Bloch,et al.  Interobserver agreement for the assessment of handicap in stroke patients. , 1988, Stroke.

[12]  B. Hopkinson,et al.  Intra-arterial thrombolysis using recombinant tissue plasminogen activator (r-TPA): the optimal agent, at the optimal dose? , 1989, European journal of vascular surgery.

[13]  J. Serfaty,et al.  Comparison of intravenous alteplase with a combined intravenous–endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE study): a prospective cohort study , 2009, The Lancet Neurology.

[14]  J. Brøgger,et al.  The effect of physiologic derangement in patients with stroke treated with thrombolysis. , 2008, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[15]  M. Chen,et al.  Intra-arterial Thrombolysis or Stent Placement During Endovascular Treatment for Acute Ischemic Stroke Leads to the Highest Recanalization Rate: Results of a Multicenter Retrospective Study , 2011, Neurosurgery.

[16]  P. Heuschmann,et al.  Predictors of in-hospital mortality in patients with acute ischemic stroke treated with thrombolytic therapy. , 2004, JAMA.

[17]  J. Marler,et al.  Measurements of acute cerebral infarction: a clinical examination scale. , 1989, Stroke.

[18]  E. López‐Cancio,et al.  Influence of antiplatelet pre‐treatment on the risk of intracranial haemorrhage in acute ischaemic stroke after intravenous thrombolysis , 2010, European journal of neurology.

[19]  J. Schulte‐Mönting,et al.  Hyperglycemia in Patients with Focal Cerebral Ischemia after Intravenous Thrombolysis: Influence on Clinical Outcome and Infarct Size , 2002, Cerebrovascular Diseases.

[20]  D. Tanné,et al.  Predictors of good outcome after intravenous tPA for acute ischemic stroke , 2001, Neurology.

[21]  Á. Chamorro,et al.  Uric Acid Levels Are Relevant in Patients With Stroke Treated With Thrombolysis , 2011, Stroke.

[22]  R. Delgado-Mederos,et al.  Statin pretreatment may increase the risk of symptomatic intracranial haemorrhage in thrombolysis for ischemic stroke: results from a case–control study and a meta-analysis , 2011, Journal of Neurology.

[23]  F. Dubas [Small vessel pathology and cerebral hemorrhage]. , 2003, Journal of neuroradiology. Journal de neuroradiologie.

[24]  R. Silbergleit,et al.  Lack of Association between Hyperglycaemia at Arrival and Clinical Outcomes in Acute Stroke Patients Treated with Tissue Plasminogen Activator , 2010, International journal of stroke : official journal of the International Stroke Society.

[25]  L. Defebvre,et al.  Intravenous Thrombolysis for Acute Cerebral Ischaemia: Comparison of Outcomes between Patients Treated at Working versus Nonworking Hours , 2010, Cerebrovascular Diseases.

[26]  V. Hachinski,et al.  Predictors of major neurologic improvement after thrombolysis in acute stroke , 2005, Neurology.

[27]  J. Arenillas,et al.  The Metabolic Syndrome Is Associated With a Higher Resistance to Intravenous Thrombolysis for Acute Ischemic Stroke in Women Than in Men , 2009, Stroke.

[28]  Sumit R. Majumdar,et al.  Admission Hyperglycemia Predicts a Worse Outcome in Stroke Patients Treated With Intravenous Thrombolysis , 2008, Diabetes Care.

[29]  H. Chandalia,et al.  STRESS HYPERGLYCAEMIA , 1984, The Lancet.

[30]  M. Reichhart,et al.  Thrombolysis in stroke patients aged 80 years and older: Swiss survey of IV thrombolysis , 2005, Neurology.

[31]  B. T. Hawkins,et al.  Increased blood–brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases , 2006, Diabetologia.

[32]  D. Singer,et al.  Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. , 2000, JAMA.

[33]  J. Grotta,et al.  Identifying patients at high risk for poor outcome after intra-arterial therapy for acute ischemic stroke. , 2009, Stroke.

[34]  Partial Complementation of Sinorhizobium meliloti bacA Mutant Phenotypes by the Mycobacterium tuberculosis BacA Protein , 2012, Journal of bacteriology.

[35]  J. Provencio Multimodal Reperfusion Therapy for Acute Ischemic Stroke: Factors Predicting Vessel Recanalization , 2008 .

[36]  P. Amarenco,et al.  Glucose Level and Brain Infarction: A Prospective Case-Control Study and Prospective Study , 2009, International journal of stroke : official journal of the International Stroke Society.

[37]  M. Kaste,et al.  Association of admission blood glucose and outcome in patients treated with intravenous thrombolysis: results from the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Register (SITS-ISTR). , 2010, Archives of Neurology.

[38]  G. Moretto,et al.  Does statin in the acute phase of ischemic stroke improve outcome after intravenous thrombolysis? A retrospective study , 2011, Journal of the Neurological Sciences.

[39]  Yong Y. He,et al.  Effect of plasma glucose on infarct size in focal cerebral ischemia‐reperfusion , 1991, Neurology.

[40]  Carlos A Molina,et al.  Impact of Admission Hyperglycemia on Stroke Outcome After Thrombolysis: Risk Stratification in Relation to Time to Reperfusion , 2004, Stroke.

[41]  H. S. Mueller,et al.  The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. , 1985, The New England journal of medicine.

[42]  A. Yoo,et al.  Prediction of adverse outcomes by blood glucose level after endovascular therapy for acute ischemic stroke. , 2011, Journal of neurosurgery.

[43]  D. Hadley,et al.  Randomized, controlled trial of insulin for acute poststroke hyperglycemia , 2010, Annals of neurology.

[44]  S. Muengtaweepongsa,et al.  Outcomes of Thai patients with acute ischemic stroke after intravenous thrombolysis , 2011, Journal of the Neurological Sciences.

[45]  Gerhard Schroth,et al.  Endovascular Therapy of 623 Patients With Anterior Circulation Stroke , 2012, Stroke.

[46]  J. Serfaty,et al.  Blood–brain barrier disruption is associated with increased mortality after endovascular therapy , 2013, Neurology.

[47]  M. Kaste,et al.  Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II) , 1998, The Lancet.

[48]  Werner Hacke,et al.  MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study , 2006, The Lancet Neurology.

[49]  R. Keep,et al.  Effect of Sustained-Mild and Transient-Severe Hyperglycemia on Ischemia-Induced Blood–Brain Barrier Opening , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[50]  P. Sandercock,et al.  Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK) , 2007, The Lancet Neurology.

[51]  R. Higashida,et al.  Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke , 2001, Neurology.

[52]  J. De Keyser,et al.  Moderate hyperglycaemia is associated with favourable outcome in acute lacunar stroke. , 2007, Brain : a journal of neurology.

[53]  J. Arenillas,et al.  Acute Hyperglycemia State Is Associated With Lower tPA-Induced Recanalization Rates in Stroke Patients , 2005, Stroke.

[54]  J. Arenillas,et al.  Body temperature and response to thrombolytic therapy in acute ischaemic stroke , 2008, European journal of neurology.

[55]  F. Aichner,et al.  Prognostic value of admission C-reactive protein in stroke patients undergoing IV thrombolysis , 2008, Journal of Neurology.

[56]  Andrew M Southerland,et al.  Considering hyperglycemia and thrombolysis in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial , 2012, Annals of the New York Academy of Sciences.

[57]  Andrew M. Demchuk,et al.  Markers of Increased Risk of Intracerebral Hemorrhage After Intravenous Recombinant Tissue Plasminogen Activator Therapy for Acute Ischemic Stroke in Clinical Practice: The Multicenter rt-PA Acute Stroke Survey , 2002, Circulation.

[58]  S. Chinn A simple method for converting an odds ratio to effect size for use in meta-analysis. , 2000, Statistics in medicine.

[59]  W. Hacke,et al.  Frequency of Increased Blood Pressure Levels During Systemic Thrombolysis and Risk of Intracerebral Hemorrhage , 2011, Stroke.

[60]  A. Demchuk,et al.  Asymptomatic Hemorrhage After Thrombolysis May Not Be Benign: Prognosis by Hemorrhage Type in the Canadian Alteplase for Stroke Effectiveness Study Registry , 2007, Stroke.

[61]  G. Christoforidis,et al.  Predictors of Hemorrhage Following Intra-Arterial Thrombolysis for Acute Ischemic Stroke: The Role of Pial Collateral Formation , 2008, American Journal of Neuroradiology.

[62]  C. Homko,et al.  Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. , 2006, Diabetes.

[63]  J. Sunshine,et al.  Older age does not increase risk of hemorrhagic complications after intravenous and/or intra-arterial thrombolysis for acute stroke. , 2008, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[64]  K. Kario,et al.  [Effects of statin use on intracranial hemorrhage and clinical outcome after intravenous rt-PA for acute ischemic stroke: SAMURAI rt-PA registry]. , 2010, Rinsho shinkeigaku = Clinical neurology.

[65]  P. Chan,et al.  Influence of Hyperglycemia on Oxidative Stress and Matrix Metalloproteinase-9 Activation After Focal Cerebral Ischemia/Reperfusion in Rats: Relation to Blood-Brain Barrier Dysfunction , 2007, Stroke.

[66]  S. Davis,et al.  Rapid Neurological Recovery after Intravenous Tissue Plasminogen Activator in Stroke: Prognostic Factors and Outcome , 2010, Cerebrovascular Diseases.

[67]  Scott E Kasner,et al.  Factors Associated With Intracerebral Hemorrhage After Thrombolytic Therapy for Ischemic Stroke: Pooled Analysis of Placebo Data From the Stroke-Acute Ischemic NXY Treatment (SAINT) I and SAINT II Trials , 2009, Stroke.

[68]  L. Wechsler,et al.  Factors Predicting Hemorrhagic Complications after Multimodal Reperfusion Therapy for Acute Ischemic Stroke , 2007, American Journal of Neuroradiology.

[69]  J. Broderick,et al.  Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial , 2002, Neurology.

[70]  F. Berthier,et al.  [Intravenous thrombolysis with rt-PA in stroke: experience of the Nice stroke unit]. , 2009, Revue neurologique.

[71]  J H Devries,et al.  Hyperglycemia: a prothrombotic factor? , 2010, Journal of thrombosis and haemostasis : JTH.

[72]  N. Salamon,et al.  Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis , 2007, Neurology.

[73]  A. Demchuk,et al.  Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. , 1999, Stroke.

[74]  W. Poewe,et al.  Recanalization after thrombolysis in stroke patients , 2007, Neurology.

[75]  J. Serfaty,et al.  Outcomes of Mechanical Endovascular Therapy for Acute Ischemic Stroke: A Clinical Registry Study and Systematic Review , 2011, Stroke.

[76]  W. Ganz,et al.  The thrombolysis in myocardial infarction (TIMI) trial. , 1985, The New England journal of medicine.

[77]  J. French,et al.  Prevalence of admission hyperglycaemia across clinical subtypes of acute stroke , 1999, The Lancet.

[78]  W. Koroshetz,et al.  Sex as a predictor of outcomes in patients treated with thrombolysis for acute stroke , 2007, Neurology.

[79]  G. Luijckx,et al.  Safety of routine IV thrombolysis between 3 and 4.5 h after ischemic stroke , 2007, Journal of the Neurological Sciences.

[80]  Dong Joon Kim,et al.  Prediction of long-term outcome by percent improvement after the first day of thrombolytic treatment in stroke patients , 2009, Journal of the Neurological Sciences.

[81]  D. Wagner,et al.  Predicting Major Neurological Improvement With Intravenous Recombinant Tissue Plasminogen Activator Treatment of Stroke , 2003, Stroke.

[82]  Very early neurologic improvement after intravenous thrombolysis. , 2010, Archives of neurology.

[83]  P. Adeleine,et al.  Early Fibrinogen Degradation Coagulopathy Is Predictive of Parenchymal Hematomas in Cerebral rt-PA Thrombolysis: A Study of 157 Cases , 2004, Stroke.

[84]  Mark W Parsons,et al.  Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study , 2002, Annals of neurology.

[85]  Wade S. Smith,et al.  Predictors of Good Clinical Outcomes, Mortality, and Successful Revascularization in Patients With Acute Ischemic Stroke Undergoing Thrombectomy: Pooled Analysis of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi MERCI Trials , 2009, Stroke.

[86]  J. Goldstein,et al.  Effect of systolic blood pressure reduction on hematoma expansion, perihematomal edema, and 3-month outcome among patients with intracerebral hemorrhage: results from the antihypertensive treatment of acute cerebral hemorrhage study. , 2010, Archives of neurology.

[87]  J. Martí-Fàbregas,et al.  Influence of Antiplatelet Pre-Treatment on the Risk of Symptomatic Intracranial Haemorrhage after Intravenous Thrombolysis , 2008, Cerebrovascular Diseases.