Christoph Gumbinger

Improved Prediction of Poor Outcome After Thrombolysis Using Conservative Definitions of Symptomatic Hemorrhage

Background and Purpose— Direct comparison of symptomatic intracerebral hemorrhage (sICH) rates among different thrombolysis studies is complicated by the variability of definitions of sICH. The prediction of outcome still remains unclear. Methods— Baseline data and clinical courses of patients treated with thrombolytic therapy were collected in a prospective database. The 3-month outcome was evaluated using the modified Rankin Scale. Results of 24-hour follow-up imaging were reevaluated by at least 2 independent raters. Four common definitions of sICH (National Institute of Neurological Disorders and Stroke [NINDS], European Cooperative Acute Stroke Study [ECASS] 2, Safe Implementation of Thrombolysis in Stroke [SITS], ECASS 3) were applied. Kappa interrater statistics were calculated. Our objective was to find the sICH definition with the highest predictive value for mortality, poor (modified Rankin Scale 5 or 6) and unfavorable (modified Rankin Scale ≥3) clinical outcome after 90 days. Results— The data of 314 patients were analyzed. The NINDS definition revealed the highest sICH rate (7.7%); the lowest rate was found for the ECASS 3 definition (3.2%) of sICH. The highest interrater agreement was found for the ECASS 2 definition (&kgr; 0.85) and the lowest for the NINDS definition (&kgr; 0.57). Patients with sICH according to the SITS definition had the highest risk for death (OR, 14.4) and poor outcome (OR, 26.6). Conclusions— None of the different definitions contains an optimal combination of prediction of mortality and outcome and a high interrater agreement rate. For the clinical evaluation of mortality, we recommend using the SITS definition; for studies needing a high interrater agreement rate, we recommend using the ECASS 2 definition. Due to the lack of 1 single optimal definition, future thrombolytic trials should preferably use different definitions.

Time to treatment with recombinant tissue plasminogen activator and outcome of stroke in clinical practice: retrospective analysis of hospital quality assurance data with comparison with results from randomised clinical trials

Objective To study the time dependent effectiveness of thrombolytic therapy for acute ischaemic stroke in daily clinical practice. Design A retrospective cohort study using data from a large scale, comprehensive population based state-wide stroke registry in Germany. Setting All 148 hospitals involved in acute stroke care in a large state in southwest Germany with 10.4 million inhabitants. Participants Data from 84 439 patients with acute ischaemic stroke were analysed, 10 263 (12%) were treated with thrombolytic therapy and 74 176 (88%) were not treated. Main outcome measures Primary endpoint was the dichotomised score on a modified Rankin scale at discharge (“favourable outcome” score 0 or 1 or “unfavourable outcome” score 2-6) analysed by binary logistic regression. Patients treated with recombinant tissue plasminogen activator (rtPA) were categorised according to time from onset of stroke to treatment. Analogous analyses were conducted for the association between rtPA treatment of stroke and in-hospital mortality. As a co-primary endpoint the chance of a lower modified Rankin scale score at discharge was analysed by ordinal logistic regression analysis (shift analysis). Results After adjustment for characteristics of patients, hospitals, and treatment, rtPA was associated with better outcome in a time dependent pattern. The number needed to treat ranged from 4.5 (within first 1.5 hours after onset; odds ratio 2.49) to 18.0 (up to 4.5 hours; odds ratio 1.26), while mortality did not vary up to 4.5 hours. Patients treated with rtPA beyond 4.5 hours (including mismatch based approaches) showed a significantly better outcome only in dichotomised analysis (odds ratio 1.25, 95% confidence interval 1.01 to 1.55) but the mortality risk was higher (1.45, 1.08 to 1.92). Conclusion The effectiveness of thrombolytic therapy in daily clinical practice might be comparable with the effectiveness shown in randomised clinical trials and pooled analysis. Early treatment was associated with favourable outcome in daily clinical practice, which underlines the importance of speeding up the process for thrombolytic therapy in hospital and before admission to achieve shorter time from door to needle and from onset to treatment for thrombolytic therapy.

Blood Pressure Variability after Intravenous Thrombolysis in Acute Stroke Does Not Predict Intracerebral Hemorrhage but Poor Outcome

Background: The relevance of blood pressure variability (BPV) in the development of intracerebral hemorrhage (ICH) after intravenous thrombolysis (IVT) in acute stroke still remains uncertain. Methods: 427 consecutive patients treated with IVT in the years 2007–2009 were studied. Blood pressure (BP) values were analyzed from admission to follow-up imaging scan and described as mean, maximum, minimum, standard deviation (SD), difference between maximum and minimum, successive variation (SV) and maximum SV. ICH was categorized based on radiologic criteria and symptomatic ICH (sICH) was defined as ICH plus worsening of the National Institute of Health Stroke Scale by ≧4 points or leading to death. Three-month outcome was described by means of the modified Rankin Scale. Results: We observed any ICH in 51 (11.9%) and sICH in 10 (2.3%) patients. Systolic and diastolic BP profiles, including mean, maximum, minimum, SD, difference between maximum and minimum, SV and maximum SV, did not differ between ICH-negative, ICH-positive and sICH patients. In univariate analysis, high systolic BPV was associated with sICH (p = 0.03). A logistic regression model to predict ICH only found early CT findings (OR = 2.74, 95% CI = 1.47–5.11, p < 0.01) as independently associated with ICH. Poor 3-month outcome was independently predicted by age (OR = 0.96, 95% CI = 0.94–0.97, p < 0.001), NIHSS on admission (OR = 0.84, 95% CI = 0.80–0.87, p < 0.001), ICH (OR = 0.29, 95% CI = 0.13–0.66, p < 0.01) and high systolic BPV (OR = 1.68, 95% CI = 1.05–2.69, p < 0.05). Conclusions: We demonstrate that high BPV in patients receiving IVT leads to poor outcome but does not increase the risk of ICH/sICH.

Asymmetry of deep medullary veins on susceptibility weighted MRI in patients with acute MCA stroke is associated with poor outcome

Background and Purpose Due to its sensitivity to deoxyhemoglobin, susceptibility weighted imaging (SWI) enables the visualization of deep medullary veins (DMV) in patients with acute stroke, which are difficult to depict under physiological circumstances. This study assesses the asymmetric appearance of prominent DMV as an independent predictor for stroke severity and outcome. Materials and Methods SWI of 86 patients with acute middle cerebral artery (MCA) stroke were included. A scoring system from 0 (no visible DMV) to 3 (very prominent DMV) was applied for both hemispheres separately. A difference of scores between ipsi- and contralateral side was defined as asymmetric (AMV+). Occurrence of AMV+ was correlated with the National Institute of Health Stroke Scale (NIHSS) Score on admission and discharge, as well as the modified Rankin Scale (mRS) at discharge. Ordinal regression analysis was used to evaluate NIHSS and mRS as predictors of stroke severity, clinical course of disease and outcome. Results 55 patients displayed AMV+ while 31 did not show an asymmetry (AMV–). Median NIHSS on admission was 17 (11–21) in the AMV+ group and 9 (5–15) in the AMV– group (p = 0.001). On discharge median NIHSS was 11 (5–20) for AMV+ and 5 (2–14) for AMV– (p = 0.005). The median mRS at discharge was 4 (3–5) in the AMV+ group and 3 (1–4) in AMV– (p = 0.001). Odds ratio was 3.19 (95% CI: 1.24–8.21) for AMV+ to achieve a higher mRS than AMV– (p = 0.016). Conclusion The asymmetric appearance of DMV on SWI is a fast and easily evaluable parameter for the prediction of stroke severity and can be used as an additional imaging parameter in patients with acute MCA stroke.

Relationship Between Onset-to-Door Time and Door-to-Thrombolysis Time: A Pooled Analysis of 10 Dedicated Stroke Centers

Background and Purpose— Inverse relationship between onset-to-door time (ODT) and door-to-needle time (DNT) in stroke thrombolysis was reported from various registries. We analyzed this relationship and other determinants of DNT in dedicated stroke centers. Methods— Prospectively collected data of consecutive ischemic stroke patients from 10 centers who received IV thrombolysis within 4.5 hours from symptom onset were merged (n=7106). DNT was analyzed as a function of demographic and prehospital variables using regression analyses, and change over time was considered. Results— In 6348 eligible patients with known treatment delays, median DNT was 42 minutes and kept decreasing steeply every year (P<0.001). Median DNT of 55 minutes was observed in patients with ODT ⩽30 minutes, whereas it declined for patients presenting within the last 30 minutes of the 3-hour time window (median, 33 minutes) and of the 4.5-hour time window (20 minutes). For ODT within the first 30 minutes of the extended time window (181–210 minutes), DNT increased to 42 minutes. DNT was stable for ODT for 30 to 150 minutes (40–45 minutes). We found a weak inverse overall correlation between ODT and DNT (R2=−0.12; P<0.001), but it was strong in patients treated between 3 and 4.5 hours (R2=−0.75; P<0.001). ODT was independently inversely associated with DNT (P<0.001) in regression analysis. Octogenarians and women tended to have longer DNT. Conclusions— DNT was decreasing steeply over the last years in dedicated stroke centers; however, significant oscillations of in-hospital treatment delays occurred at both ends of the time window. This suggests that further improvements can be achieved, particularly in the elderly.

Continuous monitoring versus HOLTER ECG for detection of atrial fibrillation in patients with stroke

Background and purpose:  Detection of atrial fibrillation is of vital importance because oral anticoagulation decreases the risk of a stroke by 64%. Current standards for stroke unit treatment require continuous electrocardiogram (ECG) monitoring for at least 24 h. Additionally, a 24‐h HOLTER ECG (HOLTER) should be performed in selected patients. It remains unclear whether continuous monitoring at the bedside is equivalent to HOLTER for the detection of atrial fibrillation. Furthermore, we investigate how many additional patients with paroxysmal atrial fibrillation can be identified as a result of a longer duration of continuous monitoring.

Prevalence of atrial fibrillation in intracerebral hemorrhage

Oral anticoagulation (OAC) is an effective preventive therapy for ischemic stroke in atrial fibrillation (AF). The management of anticoagulation in AF patients with previous intracerebral hemorrhage (ICH) is challenging. The aim of this study was to determine the prevalence of AF after acute ICH in a consecutive monocenter cohort, and to document the subsequent management with respect to OAC.

Oral Anticoagulants – A Frequent Challenge for the Emergency Management of Acute Ischemic Stroke

Background: The emergency management of patients with acute ischemic stroke (IS) using oral anticoagulants (OAC) represents a great challenge. Effective anticoagulation predisposes to bleeding and represents a contraindication for systemic thrombolysis. However, patients on OAC can receive intravenous thrombolysis with recombinant tissue-type plasminogen activator if the international normalized ratio (INR) does not exceed 1.7, but data regarding the risk of hemorrhagic complications are highly controversial. Neurointerventional recanalization of intracranial artery occlusion represents an alternative option in OAC patients with acute IS. The proportion of OAC users among consecutive patients who suffer from acute IS or transient ichemic attacks (TIA) is unknown. Methods: A prospective observational study, consecutively enrolling all patients with IS or TIA admitted to our neurological emergency room (ER), was performed between August 2009 and February 2011. Basic demographic variables, present use of OAC, severity of stroke, cardiovascular risk factors, INR values and the symptom onset to presentation time were recorded. In IS patients on OAC presenting within 4.5 h after symptom onset, management was analyzed. In thrombolysed IS patients, bleeding events were documented. Outcome was assessed after 3 months. Results: During the study period, 12,237 patients were admitted to our neurological ER. IS or TIA were diagnosed in 2,074 (16.9%). Complete data were available for 1,914 of these subjects (92.3%); 53.8% were male (median age: 72 years). 69.7% suffered IS, 30.3% TIA. OAC were being used by 8.7% of all patients. OAC patients were older than non-OAC patients (78 vs. 72 years, p < 0.001). Subtherapeutic INR values (<2.0) were found in 67.3% of OAC patients with IS. 54.8% of all OAC IS patients presented at the ER within ≤4.5 h after the event (57/104). An INR ≤1.7 – compatible with systemic thrombolysis – was present in 33/57 patients (57.9%). Recanalization therapy was performed in 21/57 patients (36.8%). No difference in symptomatic or fatal intracerebral bleedings between thrombolysed patients with and without prior OAC use was observed (p = 0.720 and 0.135, respectively). Multivariable analysis of predictors of the 3-month outcome in IS patients revealed that prior medication with OAC was neither associated with an unfavorable clinical outcome after 3 months in the whole population of stroke patients (p = 0.235) nor in patients in whom recanalization approaches were used (n = 306; p = 0.271). Conclusions: Oral anticoagulation represents a frequent challenge for the emergency manangement of IS. A considerable proportion of anticoagulated IS patients appears to be eligible for thrombolysis. Establishing standardized treatment procedures in these patients is warranted.

Intravenous thrombolysis for acute ischaemic stroke in the elderly: data from the Baden-Wuerttemberg stroke registry

In Europe intravenous thrombolysis (IVT) for ischaemic stroke is still not approved for patients aged >80 years. However, elderly patients are frequently treated based on individual decision making. In a retrospective observational study a consecutive and prospective stroke registry in southwest Germany was analysed.

Restriction of therapy mainly explains lower thrombolysis rates in reduced stroke service levels

Objective: To assess the influence of preexisting disabilities, age, and stroke service level on standardized IV thrombolysis (IVT) rates in acute ischemic stroke (AIS). Methods: We investigated standardized IVT rates in a retrospective registry-based study in 36,901 patients with AIS from the federal German state Baden-Wuerttemberg over a 5-year period. Patients admitted within 4.5 hours after stroke onset were selected. Factors associated with IVT rates (patient-level factors and stroke service level) were assessed using robust Poisson regression modeling. Interactions between factors were considered to estimate risk-adjusted mortality rates and potential IVT rates by service level (with stroke centers as benchmark). Results: Overall, 10,499 patients (28.5%) received IVT. The IVT rate declined with service level from 44.0% (stroke center) to 13.1% (hospitals without stroke unit [SU]). Especially patients >80 years of age and with preexisting disabilities had a lower chance of being treated with IVT at lower stroke service levels. Interactions between stroke service level and age group, preexisting disabilities, and stroke severity (all p < 0.0001) were observed. High IVT rates seemed not to increase mortality. Estimated potential IVT rates ranged between 41.9% and 44.6% depending on stroke service level. Conclusions: Differences in IVT rates among stroke service levels were mainly explained by differences administering IVT to older patients and patients with preexisting disabilities. This indicates considerable further potential to increase IVT rates. Our findings support guideline recommendations to admit acute stroke patients to SUs.