Risk Of Symptomatic Intracranial Hemorrhage Research Articles

Early deterioration after thrombolysis plus aspirin in acute stroke: a post hoc analysis of the Antiplatelet Therapy in Combination with Recombinant t-PA Thrombolysis in Ischemic Stroke trial.

Aspirin early after intravenous thrombolysis in acute ischemic stroke increases the risk of symptomatic intracranial hemorrhage (SICH), without influencing functional outcome at 3 months. The effect of aspirin on early neurological deterioration (END) was explored as a post hoc analysis of the randomized Antiplatelet Therapy in Combination With Recombinant t-PA Thrombolysis in Ischemic Stroke (ARTIS) trial. END, defined as a ≥4 points National Institutes of Health Stroke Scale worsening ≤24 hours after intravenous thrombolysis, was categorized into SICH (ENDSICH) and cerebral ischemia (ENDCI). Multinomial logistic regression was used to assess the effect of aspirin on END. Of the 640 patients, 31 patients (4.8%) experienced END (14 ENDSICH, 17 ENDCI). Aspirin increased the risk of ENDSICH (odds ratio, 3.73; 95% confidence interval, 1.03-13.49) but not of ENDCI (odds ratio, 1.14; 95% confidence interval, 0.44-3.00). After adjustment for other explanatory variables, the association between aspirin and ENDSICH remained significant. In this trial, there is no evidence of an early antithrombotic effect from the addition of aspirin to intravenous thrombolysis in acute ischemic stroke.

Adherence to Third European Cooperative Acute Stroke Study 3- to 4.5-hour exclusions and association with outcome: data from Get with the Guidelines-Stroke.

The American Heart Association/American Stroke Association guidelines recommend intravenous tissue-type plasminogen activator (tPA) treatment 3 to 4.5 hours from symptom onset according to criteria used in the Third European Cooperative Acute Stroke Study (ECASS III). However, ECASS III excluded certain patient groups in addition to the standard exclusions used for 0 to 3 hours in the United States: age >80 years, history of stroke and diabetes mellitus, oral anticoagulant treatment, and National Institutes of Health Stroke Scale >25. We investigated adherence to these additional exclusion criteria for patients treated 3 to 4.5 hours from onset and their association with outcome. We analyzed data from Get With The Guidelines-Stroke on 32 019 patients with ischemic stroke from 1464 hospitals who were treated with tPA ≤4.5 hours from onset from January 2009 to January 2012, excluding patients transferred from another hospital. The percent of patients meeting versus not meeting each exclusion criterion were compared between treatment time windows. Overall, 1544 of 4910 (31.5%) patients treated with tPA >3 to 4.5 hours had at least 1 of the additional exclusions, the most common was age >80 years. With the exception of prior stroke and diabetes mellitus, the percent of tPA-treated patients with each exclusion criterion was significantly lower at >3 to 4.5 hours compared with 0 to 3 hours. For each additional exclusion criterion, there was no increased risk of symptomatic intracranial hemorrhage or worse hospital outcome for patients treated >3 to 4.5 hours compared with 0 to 3 hours, after adjusting for baseline differences. Patients with ECASS III-specific exclusion criteria for the >3 to 4.5 hours window are frequently treated with tPA. The presence of the additional exclusion criteria was not associated with worse outcomes in the >3 to 4.5 hours window compared with the 0 to 3 hours window.

Thrombolysis for acute ischaemic stroke.

Most strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred and improve recovery after stroke in some people. Thrombolytic drugs, however, can also cause serious bleeding in the brain, which can be fatal. One drug, recombinant tissue plasminogen activator (rt-PA), is licensed for use in selected patients within 4.5 hours of stroke in Europe and within three hours in the USA. There is an upper age limit of 80 years in some countries, and a limitation to mainly non-severe stroke in others. Forty per cent more data are available since this review was last updated in 2009. To determine whether, and in what circumstances, thrombolytic therapy might be an effective and safe treatment for acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013) and EMBASE (1980 to November 2013). We also handsearched conference proceedings and journals, searched reference lists and contacted pharmaceutical companies and trialists. Randomised trials of any thrombolytic agent compared with control in people with definite ischaemic stroke. Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We verified the extracted data with investigators of all major trials, obtaining additional unpublished data if available. We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes.Thrombolytic therapy, mostly administered up to six hours after ischaemic stroke, significantly reduced the proportion of participants who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.78 to 0.93). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR 3.75, 95% CI 3.11 to 4.51), early death (OR 1.69, 95% CI 1.44 to 1.98; 13 trials, 7458 participants) and death by three to six months after stroke (OR 1.18, 95% CI 1.06 to 1.30). Early death after thrombolysis was mostly attributable to intracranial haemorrhage. Treatment within three hours of stroke was more effective in reducing death or dependency (OR 0.66, 95% CI 0.56 to 0.79) without any increase in death (OR 0.99, 95% CI 0.82 to 1.21; 11 trials, 2187 participants). There was heterogeneity between the trials. Contemporaneous antithrombotic drugs increased the risk of death. Trials testing rt-PA showed a significant reduction in death or dependency with treatment up to six hours (OR 0.84, 95% CI 0.77 to 0.93, P = 0.0006; 8 trials, 6729 participants) with significant heterogeneity; treatment within three hours was more beneficial (OR 0.65, 95% CI 0.54 to 0.80, P < 0.0001; 6 trials, 1779 participants) without heterogeneity. Participants aged over 80 years benefited equally to those aged under 80 years, particularly if treated within three hours of stroke. Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice.

Intravenous thrombolysis for minor stroke and rapidly improving symptoms: a quantitative overview.

Minor stroke and rapidly improving symptoms (MRIS) are usually excluded from intravenous thrombolysis (IVT) considering a possible benign prognosis and potential bleeding risk. However, its risk-benefit profile from IVT has not been fully illustrated. We searched PubMed for articles published up to December 2013 and included papers focused on the functional outcome of MRIS after IVT. The primary analysis was a comparison of the prognosis of MRIS after IVT versus non-minor stroke with IVT and MRIS without IVT, respectively. For safety analysis, the rates of symptomatic intracranial hemorrhage (SICH) and mortality were compared. Statistic calculation was conducted using the RevMan5.1 software. A total of 13 citations encompassing 2905 MRIS cases were included. Favorable discharge outcome was more frequent in non-thrombolysed MRIS than thrombolysed MRIS with an odds ratio (OR) of 0.50 (95 % CI, 0.25-0.97), while no difference was noted in the outcome after 3 months (OR 0.99; 95 % CI, 0.74-1.34). Compared with non-minor stroke, MRIS had nearly 4 times more chance to have a favorable 3-month outcome after IVT, accompanied with a lower rate of SICH (pooled rate, 3.68 % versus 5.77 %; OR 0.57; 95 % CI, 0.39-0.84). Mortality was not significantly different for MRIS with or without IVT (OR 1.21; 95 % CI, 0.54-2.72) in the included population, but was still much less than non-minor stroke after IVT (OR 0.16; 95 % CI, 0.09-0.31). MRIS patients seem not to benefit from IVT in the short-term and 3-month outcomes due to increasing early hazards. Compared with non-minor stroke, MRIS with IVT suffers a significantly lower risk of SICH and death.

The THRIVE score predicts symptomatic intracerebral hemorrhage after intravenous tPA administration in SITS-MOST.

The Totaled Health Risks in Vascular Events (THRIVE) score is a clinical prediction score that predicts ischemic stroke outcomes in patients receiving intravenous tissue plasminogen activator, endovascular stroke treatment, or no acute therapy. We have previously found an association between THRIVE and risk of post-tissue plasminogen activator symptomatic intracranial hemorrhage in the National Institute of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator trial and risk of radiographic hemorrhage in Virtual International Stroke Trials Archive. The study aims to validate the relationship between THRIVE and symptomatic intracranial hemorrhage among tissue plasminogen activator-treated patients in the large Safe Implementation of Thrombolysis in Stroke - Monitoring Study (SITS-MOST). This is a retrospective analysis of the prospective SITS-MOST to examine the relationship between THRIVE and symptomatic intracranial hemorrhage after tissue plasminogen activator treatment. Symptomatic intracranial hemorrhage after tissue plasminogen activator was defined according to each of three standard definitions: the NINDS, European Cooperative Acute Stroke Study (ECASS), and Safe Implementation of Thrombolysis in Stroke (SITS) criteria. Multivariable logistic regression was used to confirm the relationship of THRIVE and individual THRIVE components with the risk of symptomatic intracranial hemorrhage and to examine the relationship of THRIVE, symptomatic intracranial hemorrhage, and functional outcome. The odds ratio for symptomatic intracranial hemorrhage at each increased level of THRIVE score is 1·34 (95% CI 1·27 to 1·41, P < 0·001) for symptomatic intracranial hemorrhage by NINDS criteria, 1·36 (95% CI 1·27 to 1·46, P < 0·001) for symptomatic intracranial hemorrhage by ECASS criteria, and 1·21 (95% CI 1·09 to 1·36, P < 0·001) for symptomatic intracranial hemorrhage by SITS criteria. In receiver-operator characteristics analysis, the C-statistic for THRIVE prediction of symptomatic intracranial hemorrhage was 0·65 (95% CI 0·62 to 0·67) for symptomatic intracranial hemorrhage by NINDS criteria, 0·66 (95% CI 0·63 to 0·69) for symptomatic intracranial hemorrhage by ECASS criteria, and 0·61 (95% CI 0·56 to 0·66) for symptomatic intracranial hemorrhage by SITS criteria. Each component of the THRIVE score predicts the risk of symptomatic intracranial hemorrhage, with independent impact of each component in multivariable analysis. The THRIVE score predicts the risk of symptomatic intracranial hemorrhage after intravenous tissue plasminogen activator administration. This external validation of the relationship between THRIVE and symptomatic intracranial hemorrhage in a prospective study further strengthens the role of the THRIVE score in the prediction of poststroke outcomes.

Standard-Dose Intravenous Tissue-Type Plasminogen Activator for Stroke Is Better Than Low Doses

It remains uncertain whether lower dose intravenous tissue-type plasminogen activator (tPA) for stroke is as effective and safe as the standard dose. We analyzed data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China). Patients who were treated within 4.5 hours after symptom onset were included. These patients were divided into 5 groups according to tPA doses given: <0.5, 0.5 to 0.7, 0.7 to 0.85, 0.85 to 0.95, and ≥0.95 mg/kg. Symptomatic intracranial hemorrhage, mortality, and 90-day outcome assessed by modified Rankin scale were analyzed. A total of 919 patients were enrolled. Among them, 9 had <0.5 mg/kg, 75 had 0.5 to 0.7 mg/kg, 131 had 0.7 to 0.85 mg/kg, 678 had 0.85 to 0.95 mg/kg, and 26 had ≥0.95 mg/kg. Because of sample sizes, only 0.5 to 0.7, 0.7 to 0.85, and 0.85 to 0.95 mg/kg groups were compared. Median tPA doses were 0.64, 0.79, and 0.90 mg, respectively. After adjustment for the baseline variables, there were no significant differences in mortality(5.41% versus 8.66% versus 7.36%; P=0.695) and symptomatic intracranial hemorrhage (0% versus 3.82% versus 1.46%; P=0.106). The 0.5 to 0.7 mg/kg group had less excellent recovery outcome (modified Rankin scale, 0-1) than 0.85 to 0.95 mg/kg group (41.89% versus 53.83%; odds ratio=0.58; P=0.031) at 90 days. The 0.70 to 0.85 mg/kg group had less functional independence outcome (modified Rankin scale, 0-2) than 0.85 to 0.95 mg/kg group (54.33% versus 64.51%; odds ratio=0.66; P=0.036) at 90 days. Our study suggests that standard-dose intravenous tPA for stroke had more favorable outcome without increasing the risk of symptomatic intracranial hemorrhage than low-dose tPA. For Asian people, 0.9 mg/kg should be the optimal dose of tPA to treat acute ischemic stroke.

Abstract 7: Risk of Intracranial Hemorrhage Among Acute Ischemic Stroke Patients Receiving Prior Antiplatelet Therapy and Treated with Intravenous Tissue Plasminogen Activator

Background: Intravenous tissue plasminogen activator (tPA) is known to improve outcomes in ischemic stroke. However, patients receiving long-term antiplatelet therapy may face an increased risk of symptomatic intracranial hemorrhage (sICH) when treated with tPA. While current guidelines allow use of tPA in patients on antiplatelet therapy, there are limited data on the safety of tPA in this population. Methods: Data from 51,922 ischemic stroke patients treated with tPA within 4.5 hours of symptom onset from 1,401 Get With The Guidelines-Stroke hospitals between January 2009 and June 2013 were analyzed. Multivariate logistic regression model with generalized estimating equations approach was performed to evaluate the association of preadmission antiplatelet therapy on sICH risk. Results: Of tPA treated patients 23,232 (45%) were receiving antiplatelet medicine prior to admission. Patients on prior antiplatelet therapy were older (median 76 vs. 68 years, p&lt;.001), had more comorbid illness (CAD/prior MI, prior stroke/TIA, atrial fibrillation, diabetes, dyslipidemia, hypertension and heart failure, all p &lt;.001) but had similar stroke severity (median National Institutes of Health Stroke Scale [NIHSS] 10 vs. 10, p=0.07). Crude rates of sICH were higher in those on prior antiplatelet therapy 5.32% vs. 4.03% (unadjusted OR 1.31, 95% CI 1.20-1.43). Multivariate analysis revealed that prior antiplatelet therapy was an independent predictor of sICH (adjusted OR 1.17, 95% CI 1.06-1.29; adjusted sICH rates 4.93% vs. 4.26%), serious systemic hemorrhage or any tPA complications. These findings were consistent in subgroup analysis of 0-3 hour treatment window. However, there were no significant differences between two groups in mortality, discharge to skilled nursing facility or hospice. In contrast, antiplatelet therapy was associated with favorable ambulatory status at discharge after risk adjustment ( Table ). Conclusion: This study represents the largest clinical experience of the safety of thrombolysis in patients on prior antiplatelet therapy. Despite a higher incidence of sICH, the absolute excess risk appears small (0.67%). These findings support current guideline recommendations regarding use of intravenous tPA in patients on antiplatelet therapy with careful weighing of potential risk and benefit.

North American SOLITAIRE Stent-Retriever Acute Stroke Registry

Previous work that predated the availability of the safer stent-retriever devices has suggested that general anesthesia (GA) may have a negative impact on outcomes in patients with acute ischemic stroke undergoing endovascular therapy. We reviewed demographic, clinical, procedural (GA versus local anesthesia [LA], etc), and site-adjudicated angiographic and clinical outcomes data from consecutive patients treated with the Solitaire FR device in the investigator-initiated North American SOLITAIRE Stent-Retriever Acute Stroke (NASA) Registry. The primary outcomes were 90-day modified Rankin Scale, mortality, and symptomatic intracranial hemorrhage. A total of 281 patients from 18 centers were enrolled. GA was used in 69.8% (196/281) of patients. Baseline demographic and procedural factors were comparable between the LA and GA groups, except the former demonstrated longer time-to-groin puncture (395.4±254 versus 337.4±208 min; P=0.04), lower National Institutes of Health Stroke Scale (NIHSS; 16.2±5.8 versus 18.8±6.9; P=0.002), lower balloon-guide catheter usage (22.4% versus 49.2%; P=0.0001), and longer fluoroscopy times (39.5±33 versus 28±22.8 min; P=0.008). Recanalization (thrombolysis in cerebral infarction ≥2b; 72.94% versus 73.6%; P=0.9) and rate of symptomatic intracranial hemorrhage (7.1% versus 11.2%; P=0.4) were similar but modified Rankin Scale ≤2 was achieved in more LA patients, 52.6% versus 35.6% (odds ratio, 1.4 [1.1-1.8]; P=0.01). In multivariate analysis, hypertension, NIHSS, unsuccessful revascularization, and GA use (odds ratio, 3.3 [1.6-7.1]; P=0.001) were associated with death. When only anterior circulation and elective GA patients were included, there was a persistent difference in good outcomes in favor of LA patients (50.7% versus 35.5%; odds ratio, 1.3 [1.01-1.6]; P=0.04). The NASA Registry has demonstrated that clinical outcomes and survival are significantly better in patients treated with LA, without increased symptomatic intracranial hemorrhage risk. Future trials should prospectively evaluate the effect of GA on outcomes.

Predicting outcomes after transient ischemic attack and stroke.

Predicting functional outcome and mortality after stroke, with or without thrombolysis, is a critical role of neurologists. This article reviews the predictors of outcome after ischemic stroke. Several scores were recently designed to predict (1) mortality and poor functional outcome after ischemic stroke, (2) the functional outcome and risk of symptomatic intracranial hemorrhage (sICH) after thrombolysis, and (3) the risk of stroke following TIA. Validation of these prediction instruments is ongoing, and studies will be critical to determine the general applicability of these scores. Although several scores were developed to predict mortality and outcome after stroke, it may be premature to employ these prediction scores to determine individual patient outcome. Similarly, prediction scores should not be used to deny patients tissue plasminogen activator (tPA), even if the scores predict that the patient has a high likelihood of sICH or poor outcome after thrombolysis.

Role of Preexisting Disability in Patients Treated With Intravenous Thrombolysis for Ischemic Stroke

Little is known about the effect of thrombolysis in patients with preexisting disability. Our aim was to evaluate the impact of different levels of prestroke disability on patients' profile and outcome after intravenous thrombolysis. We analyzed the data of all stroke patients admitted between October 2003 and December 2011 that were contributed to the Safe Implementation of Treatments in Stroke-Eastern Europe (SITS-EAST) registry. Patients with no prestroke disability at all (modified Rankin Scale [mRS] score, 0) were used as a reference in multivariable logistic regression. Of 7250 patients, 5995 (82%) had prestroke mRS 0, 791 (11%) had prestroke mRS 1, 293 (4%) had prestroke mRS 2, and 171 (2%) had prestroke mRS≥3. Compared with patients with mRS 0, all other groups were older, had more comorbidities, and more severe neurological deficit on admission. There was no clear association between preexisting disability and the risk of symptomatic intracranial hemorrhage. Prestroke mRS 1, 2, and ≥3 were associated with increased risk of death at 3 months (odds ratio, 1.3, 2.0, and 2.6, respectively) and lower chance of achieving favorable outcome (achieving mRS 0-2 or returning to the prestroke mRS; 0.80, 0.41, 0.59, respectively). Patients with mRS≥3 and 2 had similar vascular profile and favorable outcome (34% versus 29%), despite higher mortality (48% versus 39%). Prestroke disability does not seem to independently increase the risk of symptomatic intracranial hemorrhage after thrombolysis. Despite higher mortality, 1 in 3 previously disabled patients may return to his/her prestroke mRS. Therefore, they should not be routinely excluded from thrombolytic therapy.

Abstract W P241: Early Anti-Coagulation in Acute Cardio-Embolic Stroke is Safe But Does Not Prevent Recurrent Stroke: A Single Centre Review

Background: Atrial fibrillation is the most common arrhythmia in older adults and a common cause of stroke. Patients with acute cardio-embolic stroke from atrial fibrillation are at high risk for recurrence with up to 50% of recurrent stroke occurring within 2 weeks of the index event. Anti-coagulation with heparinoids within 48 hours of stroke has been shown to increase risk of symptomatic intracranial hemorrhage (ICH) with no clear benefit on early stroke recurrence. Methods: This study was a retrospective chart review of consecutive patients who were admitted to the stroke service at the Foothills Medical Centre between 2009 and 2011. All patients with an acute stroke with a cardio-embolic etiology and a diagnosis of atrial fibrillation either by history or on electrocardiogram within two years of stroke were reviewed. We hypothesized that anti-coagulation within two weeks of stroke, appropriately begun because of a diagnosis of atrial fibrillation, decreased rates of recurrent stroke without causing an increase in rates of symptomatic ICH. Results: During the three-year period 324 patients were identified with cardio-embolic stroke secondary to atrial fibrillation. Within two weeks of stroke onset 63.0% (203/324) of patients were therapeutic on anti-coagulation with warfarin being the most common anti-coagulant used (67.6%). Patients who were anti-coagulated had a smaller mean stroke volume (18.9 cc vs 49 cc) and lower mean NIHSS at presentation (7 vs 9) but otherwise did not differ in baseline characteristics. Three (0.9%) patients had a clinically significant ICH; only one patient was actively anti-coagulated at the time of ICH, one was taking aspirin only and one was on aspirin and low dose enoxaparin for prevention of deep vein thrombosis. Recurrent stroke occurred in 16 patients (4.9%) within the two-week period. Anti-coagulation did not significantly reduce the risk of recurrent stroke (RR 0.67 95% CI 0.19 - 2.36). Conclusion: Anti-coagulation within 2 weeks of acute stroke in patients with atrial fibrillation appears to be safe among patients with smaller infarcts. Large studies would be needed to show if anticoagulation actually reduced the rate of early recurrent cardioembolic stroke.

Abstract W P54: Renal Impairment in African American Stroke Patients and the Risk of Symptomatic ICH With Systemic tPA

Background: Uremia is a bleeding risk in chronic kidney disease (CKD) that has a higher prevalence among African Americans (AA). Recent studies in predominantly Caucasian populations showed that impaired renal function did not increase the risk of symptomatic intracranial hemorrhage (sICH) with intravenous tPA for acute ischemic stroke. We sought to determine if the risk of sICH is higher in AA patients with CKD at our institution. Subjects &amp; Methods: Consecutive patients who received intravenous thrombolysis at our comprehensive stroke center were retrospectively analyzed. Demographics, stroke severity, and instances of sICH were recorded. Renal function was assessed by creatinine clearance (CrCl) and estimated with the Cockcroft and Gault equation. CKD was defined as CrCl &lt; 60. CrCl was further stratified into the following groups: 59 - 30, 29 - 15, and &lt; 15 ml/min. Results: We identified 236 patients with reported CrCl who received tPA at our institution (mean age 65+/-17 SD, 46% women, pre-treatment median NIHSS 5; IQR 8) and CKD was documented in 90/236 (38%) of all tPA-treated patients. AA patients comprised 36% (86/236) of the study population with 37 (43%) diagnosed with CKD, p=0.23 AA vs rest. Among all patients with CKD (n=90), 83% had CrCl between 59 - 30 ml/min, 9% had 29 - 15 ml/min and 8% had &lt;15 ml/min CrCl range. sICH occurred in 2/90 (2.2%) of all patients with CKD (both in 30-59 ml/min group) compared to 4/146 (2.7%) without CKD (NS). sICH among AA patients with or without CKD was 2.7% and 2% respectively (NS). Conclusions: Our data are consistent with previous studies that severe renal impairment did not result in higher risk of sICH since the enzymatic activity of tPA may be limited by uremia. Although limited by relatively small numbers, our analysis did not show an increased sICH risk due to any renal impairment or AA race.

Abstract T P65: Prior Stroke but Not Diabetes Mellitus Is Associated with Symptomatic Intracranial Hemorrhage after Rt-PA Administration

Introduction: The European drug license for rt-PA considers diabetes plus previous stroke as an exclusion criterion for the administration of the treatment due to an increased risk of symptomatic intracranial hemorrhage (SICH). However, given that data from different studies have not confirmed this association, we were interested in analyzing whether the presence of these pathologies was associated with the development of SICH in our population of rt-PA-treated patients. Patients and methods: For the purpose of this study, we evaluated 667 patients treated with rt-PA at our center between October 1999 and December 2012. The existence of bleeding was assessed in the cranial CT performed at 24±12 h after rt-PA administration and was considered to be symptomatic when it was associated with neurological deterioration, which was defined as an increase ≥4 points in the NIHSS. Previous history of diabetes and stroke was collected from all patients. Results: 176 (26.4%) had hemorrhagic transformation (HT), which was symptomatic in 30 cases (4.5%). In the univariate analysis, neither diabetes and previous stroke together, nor alone, were associated with HT. However, previous stroke (10% vs. 4%, p=0.028) but not diabetes or both, was associated with SICH. After adjustment for the rest of the variables associated with the development of SICH, only the history of prior stroke remained as an independent predictor of this complication (OR 4.3;CI 95%, 1.12-16.19; p=0.03). Conclusions: In our large cohort of patients treated with rt-PA, only a prior history of stroke predicted the development of SICH. No association was found with diabetes.

Abstract T MP104: The Role of Antithrombotics Therapy in Recent Ischaemic Stroke Patients with Atrial Fibrillation: Analysis from VISTA

Background and Purpose: There is uncertainty on the optimal latency after acute ischaemic stroke at which antithrombotic treatment should commence for atrial fibrillation (AF) patients, in order to prevent recurrent stroke (RS) without provoking symptomatic intracranial haemorrhage (SICH). We sought to describe the risk factors and patterns of RS and SICH in a cohort of patients with AF and recent stroke. Methods: We assessed the association of antihrombotic treatment (i.e. anticoagulants and antiplatelets) with the distribution of the modified Rankin Scale (mRS) at day 90, and the occurrence of RS and SICH. We developed statistical models for the prediction of RS and SICH in the first 90 days after stroke, using univariate and multivariate analysis. Results: Data were available for 1,644 patients. Combined antithrombotic therapy with both anticoagulation and antiplatelet (n=782) was associated with more favourable functional outcome across full scale mRS OR=1.785 (95% CI: 1.316, 2.421; P=0.0002), and significantly lower risk of mortality by day 90, SICH by day 90 and RS by day 90: Mortality day 90 OR=0.344 (95% CI: 0.235, 0.502; P&lt;0.0001), SICH day 90 OR=0.18 (95% CI: 0.086, 0.37; P&lt;0.0001) and RS day 90 OR=0.33 (95% CI: 0.21, 0.53; P&lt;0.0001). Patients with ischaemic stroke who had high baseline glucose had a high risk of both RS and SICH events after stroke. Additionally, patients who had increased neurological impairment, previous history of TIA and received no antithrombotic treatment were at increased risk of RS. The relative risk of RS versus SICH appeared constant over time. Conclusions: It seems justified to initiate anticoagulation immediately the patient attains medical and neurological stability, taking into account the potential of haemorrhagic transformation as part of the natural progression in stroke and the increasing risk of recurrent stroke with time if left untreated. Antiplatelet treatment pending introduction of anticoagulation is reasonable.

Symptomatic Intracranial Hemorrhage After Stroke Thrombolysis

Several prognostic scores have been developed to predict the risk of symptomatic intracranial hemorrhage (sICH) after ischemic stroke thrombolysis. We compared the performance of these scores in a multicenter cohort. We merged prospectively collected data of patients with consecutive ischemic stroke who received intravenous thrombolysis in 7 stroke centers. We identified and evaluated 6 scores that can provide an estimate of the risk of sICH in hyperacute settings: MSS (Multicenter Stroke Survey); HAT (Hemorrhage After Thrombolysis); SEDAN (blood sugar, early infarct signs, [hyper]dense cerebral artery sign, age, NIH Stroke Scale); GRASPS (glucose at presentation, race [Asian], age, sex [male], systolic blood pressure at presentation, and severity of stroke at presentation [NIH Stroke Scale]); SITS (Safe Implementation of Thrombolysis in Stroke); and SPAN (stroke prognostication using age and NIH Stroke Scale)-100 positive index. We included only patients with available variables for all scores. We calculated the area under the receiver operating characteristic curve (AUC-ROC) and also performed logistic regression and the Hosmer-Lemeshow test. The final cohort comprised 3012 eligible patients, of whom 221 (7.3%) had sICH per National Institute of Neurological Disorders and Stroke, 141 (4.7%) per European Cooperative Acute Stroke Study II, and 86 (2.9%) per Safe Implementation of Thrombolysis in Stroke criteria. The performance of the scores assessed with AUC-ROC for predicting European Cooperative Acute Stroke Study II sICH was: MSS, 0.63 (95% confidence interval, 0.58-0.68); HAT, 0.65 (0.60-0.70); SEDAN, 0.70 (0.66-0.73); GRASPS, 0.67 (0.62-0.72); SITS, 0.64 (0.59-0.69); and SPAN-100 positive index, 0.56 (0.50-0.61). SEDAN had significantly higher AUC-ROC values compared with all other scores, except for GRASPS where the difference was nonsignificant. SPAN-100 performed significantly worse compared with other scores. The discriminative ranking of the scores was the same for the National Institute of Neurological Disorders and Stroke, and Safe Implementation of Thrombolysis in Stroke definitions, with SEDAN performing best, GRASPS second, and SPAN-100 worst. SPAN-100 had the worst predictive power, and SEDAN constantly the highest predictive power. However, none of the scores had better than moderate performance.

Combination approaches to attenuate hemorrhagic transformation after tPA thrombolytic therapy in patients with poststroke hyperglycemia/diabetes.

To date, tissue type plasminogen activator (tPA)-based thrombolytic stroke therapy is the only FDA-approved treatment for achieving vascular reperfusion and clinical benefit, but this agent is given to only about 5% of stroke patients in the USA. This may be related, in part, to the elevated risk of symptomatic intracranial hemorrhage, and consequently limited therapeutic time window. Clinical investigations demonstrate that poststroke hyperglycemia is one of the most important risk factors that cause intracerebral hemorrhage and worsen neurological outcomes. There is a knowledge gap in understanding the underlying molecular mechanisms, and lack of effective therapeutics targeting the severe complication. This short review summarizes clinical observations and experimental investigations in preclinical stroke models of the field. The data strongly suggest that interactions of multiple pathogenic factors including hyperglycemia-mediated vascular oxidative stress and inflammation, ischemic insult, and tPA neurovascular toxicity in concert contribute to the BBB damage-intracerebral hemorrhagic transformation process. Development of combination approaches targeting the multiple pathological cascades may help to attenuate the hemorrhagic complication.

Serum Creatinine May Indicate Risk of Symptomatic Intracranial Hemorrhage After Intravenous Tissue Plasminogen Activator (IV tPA)

Symptomatic intracranial hemorrhage (sICH) is a known complication following administration of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke. sICH results in high rates of death or long-term disability. Our ability to predict its occurrence is important in clinical decision making and when counseling families. The initial National Institute of Neurological Disorders and Stroke (NINDS) investigators developed a list of relative contraindications to IV tPA meant to decrease the risk of subsequent sICH. To date, the impact of renal impairment has not been well studied. In the current study we evaluate the potential association between renal impairment and post-tPA intracranial hemorrhage (ICH).Admission serum creatinine and estimated glomerular filtration rate (eGFR) were recorded in 224 patients presenting within 4.5 hours from symptom onset and treated with IV tPA based on NINDS criteria. Neuroimaging was obtained 1 day post-tPA and for any change in neurologic status to evaluate for ICH. Images were retrospectively evaluated for hemorrhage by a board-certified neuroradiologist and 2 reviewers blinded to the patient’s neurologic status. Medical records were reviewed retrospectively for evidence of neurologic decline indicating a “symptomatic” hemorrhage. sICH was defined as subjective clinical deterioration (documented by the primary neurology team) and hemorrhage on neuroimaging that was felt to be the most likely cause. Renal impairment was evaluated using both serum creatinine and eGFR in a number of ways: 1) continuous creatinine; 2) any renal impairment by creatinine (serum creatinine >1.0 mg/dL); 3) continuous eGFR; and 4) any renal impairment by eGFR (eGFR <60 mL/min per 1.73 m2). Student paired t tests, Fisher exact tests, and multivariable logistic regression (adjusted for demographics and vascular risk factors) were used to evaluate the relationship between renal impairment and ICH.Fifty-seven (25%) of the 224 patients had some evidence of hemorrhage on neuroimaging. The majority of patients were asymptomatic. Renal impairment (defined by serum creatinine >1.0 mg/dL) was not associated with combined symptomatic and asymptomatic intracranial bleeding (p = 0.359); however, there was an adjusted 5.5-fold increased odds of sICH when creatinine was >1.0 mg/dL (95% confidence interval, 1.08–28.39), and the frequency of sICH for patients with elevated serum creatinine was 10.6% (12/113), versus 1.8% (2/111) in those with normal renal function (p = 0.010).Our study suggests that renal impairment is associated with higher risk of sICH after administration of IV tPA. As IV tPA is an important and effective treatment for acute ischemic stroke, a multicenter study is needed to determine whether the observation that renal dysfunction is associated with sICH from this retrospective study holds true in a larger prospective trial.

The risks and benefits of RTPA in acute ischemic stroke for patients at high risk of intracranial haemorrhage and poor functional outcome: a secondary analysis of the IST-3 trial and systematic review of prediction models

Background Treating acute ischaemic stroke patients with iv-rtPA is of overall benefit. An associated increase in the risk of symptomatic intracranial haemorrhage (SICH) may cause considerable harm. We investigated (i) whether novel or existing prediction models could predict SICH or poor functional outcome in rtPA treated patients and (ii) whether ischemic stroke patients at either a high predicted risk of SICH or poor functional outcome experienced less benefit from rtPA.

Validation of the SEDAN Score to Predict Risk of Symptomatic Intracranial Hemorrhage after Stroke Thrombolysis

Validation of the SEDAN Score to Predict Risk of Symptomatic Intracranial Hemorrhage after Stroke Thrombolysis

Abstract 234: Prior Warfarin Treatment and Intracranial Hemorrhage among Patients With Acute Ischemic Stroke Treated With Intravenous Tissue Plasminogen Activator: A Meta-analysis

Background and Purpose: The risk for bleeding complications after intravenous thrombolysis for ischemic stroke in patients on warfarin with international normalized ratio [INR] ≤1.7) remains unclear. The aim of the current study is to perform a meta-analysis to determine whether there is an association between warfarin and risk of symptomatic intracranial hemorrhage (sICH). Methods: We searched MEDLINE, Web of Science and EBSCO databases for articles published through Jul 2012. A random-effects model was used to compute the pooled risk estimate. Results: Overall, 11 observational studies were identified that met our study inclusion criteria. This included 29,283 stroke participants treated with tPA; of which 2129 (7.3%) patients were on home warfarin prior treatment. Warfarin pretreatment was associated with an increased crude OR for symptomatic intracranial hemorrhage (sICH) (combined OR=1.77; 95% CI, 1.07~2.93;P=0.03).Of these studies, 7 studies had conducted a multivariate adjusted analyses, which demonstrated no association between warfarin use and increased risk of sICH following tPA use (combined adjusted OR=1.73; 95% CI, 0.91-3.28; p=0.10). Conclusions: These data suggested that the risk of sICH after thrombolytic therapy is not increased in patients using warfarin with sub therapeutic INR levels.