Subtherapeutic International Normalized Ratio in Warfarin-Treated Patients Increases the Risk for Symptomatic Intracerebral Hemorrhage After Intravenous Thrombolysis

211

204

Background and Purpose-There are few validated models for prediction of risk of symptomatic intracranial hemorrhage (sICH) after intravenous tissue-type plasminogen activator treatment for ischemic stroke. We used data from Get With The Guidelines-Stroke (GWTG-Stroke) to derive and validate a prediction tool for determining sICH risk. Methods-The population consisted of 10 242 patients from 988 hospitals who received intravenous tissue-type plasminogen activator within 3 hours of symptom onset from January 2009 to June 2010. This sample was randomly divided into derivation (70%) and validation (30%) cohorts. Multivariable logistic regression identified predictors of intravenous tissue-type plasminogen activator-related sICH in the derivation sample; model ␤ coefficients were used to assign point scores for prediction. Results-sICH within 36 hours was noted in 496 patients (4.8%). Multivariable adjusted independent predictors of sICH were increasing age (17 points), higher baseline National Institutes of Health Stroke Scale (42 points), higher systolic blood pressure (21 points), higher blood glucose (8 points), Asian race (9 points), and male sex (4 points). The C-statistic was 0.71 in the derivation sample and 0.70 in the independent internal validation sample. Plots of observed versus predicted sICH showed good model calibration in the derivation and validation cohorts. The model was externally validated in National Institute of Neurological Disorders and Stroke trial patients with a C-statistic of 0.68. Conclusions-The GWTG-Stroke sICH risk "GRASPS" score provides clinicians with a validated method to determine the risk of sICH in patients treated with intravenous tissue-type plasminogen activator within 3 hours of stroke symptom onset. (Stroke. 2012;43:2293-2299.)

Section: Discussionsupporting

confidence: 81%

Risk Score for Intracranial Hemorrhage in Patients With Acute Ischemic Stroke Treated With Intravenous Tissue-Type Plasminogen Activator

Menon

Saver²,

Prabhakaran³

et al. 2012

211

204

“…Two relatively small multicenter registries and several single-center case series have shown widely varied rates of sICH (0%-36%) in patients taking warfarin with subtherapeutic INR at the time of thrombolysis. 157,177,[179][180][181][182][183][184][185][186] In 2 meta-analyses, the larger of which included 284 patients, the OR for sICH was increased for warfarin-treated patients (OR, 2.6; 95% CI, 1.1-5.9; and aOR, 4.1; 95% CI, 1-16.1), but both of these analyses were not adjusted for potential confounders. 184,187 Data from 2 large registries (GWTG and Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register [SITS-ISTR]) indicate that although patients on warfarin do have higher crude rates of sICH than those not taking warfarin, when confounders such as stroke severity, older age, and comorbidities are considered, warfarin treatment with subtherapeutic INR does not independently increase the risk of sICH.…”

Section: Warfarinmentioning

confidence: 99%

Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke

Demaerschalk¹,

Kleindorfer²,

Adeoye³

et al. 2016

585

237

Purpose-To critically review and evaluate the science behind individual eligibility criteria (indication/inclusion and contraindications/exclusion criteria) for intravenous recombinant tissue-type plasminogen activator (alteplase) treatment in acute ischemic stroke. This will allow us to better inform stroke providers of quantitative and qualitative risks associated with alteplase administration under selected commonly and uncommonly encountered clinical circumstances and to identify future research priorities concerning these eligibility criteria, which could potentially expand the safe and judicious use of alteplase and improve outcomes after stroke. Methods-Writing group members were nominated by the committee chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association's Manuscript Oversight Committee. The writers used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge and, when appropriate, formulated recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on and approved the final version of this document. The document underwent extensive American Heart Association internal peer review, Stroke The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on September 24, 2015, and the American Heart Association Executive Committee on October 5, 2015. A copy of the document is available at http://my.americanheart.org/statements by selecting either the "By Topic" link or the "By Publication Date" link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com.The online-only Data Supplement, which contains literature search strategies and Figures A, B, and C, is available with this article at http://circ. ahajournals.org/lookup/suppl/doi:10.1161/STR.0000000000000086/-/DC1.The American Heart Association requests that this document be cited as follows: Demaerschalk BM, Kleindorfer DO, Adeoye OM, Demchuk AM, Fugate JE, Grotta JC, Khalessi AA, Levy EI, Palesch YY, Prabhakaran S, Saposnik G, Saver JL, Smith EE; on behalf of the American Heart Association Stroke Council and Council on Epidemiology and Prevention. Scientific rational...

“…However, warfarin-treated patients have a higher incidence of symptomatic intracerebral hemorrhage after tPA treatment, despite a PT-international normalized ratio <1.7, compared with those not taking warfarin. 3,4 In contrast, warfarin use is not associated with secondary intracerebral hemorrhage after tPA treatment in patients with acute ischemic stroke with a PT-international normalized ratio <1.7. [5][6][7] In the Japan post-Marketing Alteplase Registration Study, 8 3.5% of patients showed symptomatic intracranial hemorrhage.…”

mentioning

confidence: 98%

Rivaroxaban and Apixaban Reduce Hemorrhagic Transformation After Thrombolysis by Protection of Neurovascular Unit in Rat

Kono

Yamashita

Deguchi

et al. 2014

Background and Purpose-This study aimed to assess the risk and benefit of tissue-type plasminogen activator treatment after oral anticoagulation with rivaroxaban or apixaban compared with warfarin or placebo. Methods-Pretreatment with warfarin (0.2 mg/kg per day), rivaroxaban (2 mg/kg per day), apixaban (10 mg/kg per day), or vehicle (0.5% carboxymethyl cellulose sodium salt) was performed for 7 days. Transient middle cerebral artery occlusion was then induced for 120 minutes, followed by reperfusion with tissue-type plasminogen activator (10 mg/ kg per 10 mL). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. Twenty-four hours after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and matrix metalloproteinase-9 activity was measured by zymography. Results-The paraparesis score was significantly improved in the rivaroxaban-pretreated group compared with the warfarinpretreated group. Intracerebral hemorrhage was observed in the warfarin-pretreated group, and this was reduced in the rivaroxaban and apixaban-pretreated groups compared with the vehicle group. Marked dissociation of astrocyte foot processes and the basal lamina or pericytes was observed in the warfarin-pretreated group, and this was improved in the rivaroxaban and apixaban-pretreated groups. Furthermore, activation of matrix metalloproteinase-9 in the ipsilateral warfarin-pretreated brain was greatly reduced in rivaroxaban-and apixaban-pretreated rats. Conclusions-This study shows a lower risk of intracerebral hemorrhage after tissue-type plasminogen activator treatment in rats with ischemic stroke that are pretreated with rivaroxaban and apixaban compared with pretreatment with warfarin. Reducing neurovascular dissociation by rivaroxaban and apixaban compared with warfarin could partly explain a reduction in hemorrhagic complications reported in clinical studies.