Martin Köhrmann

Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST).

Background and Purpose— The Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) unadjusted results demonstrated that intravenous alteplase is well tolerated and that the effects were comparable with those seen in randomized, controlled trials (RCTs) when used in routine clinical practice within 3 hours of ischemic stroke onset. We aimed to identify outcome predictors and adjust the outcomes of the SITS-MOST to the baseline characteristics of RCTs. Methods— The study population was SITS-MOST (n=6483) and pooled RCTs (n=464) patients treated with intravenous alteplase within 3 hours of stroke onset. Multivariable, backward stepwise regression analyses (until P≤0.10) were performed to identify the outcome predictors for SITS-MOST. Variables appearing either in the final multivariable model or differing (P<0.10) between SITS-MOST and RCTs were included in the prediction model for the adjustment of outcomes. Main outcome measures were symptomatic intracerebral hemorrhage, defined as National Institutes of Health Stroke Scale deterioration ≥1 within 7 days with any hemorrhage (RCT definition), mortality, and independency as defined by modified Rankin Score of 0 to 2 at 3 months. Results— The adjusted proportion of symptomatic intracerebral hemorrhage for SITS-MOST was 8.5% (95% CI, 7.9 to 9.0) versus 8.6% (6.3 to 11.6) for pooled RCTs; mortality was 15.5% (14.7 to 16.2) versus 17.3% (14.1 to 21.1); and independency was 50.4% (49.6 to 51.2) versus 50.1% (44.5 to 54.7), respectively. In the multivariable analysis, older age, high blood glucose, high National Institutes of Health Stroke Scale score, and current infarction on imaging scans were related to poor outcome in all parameters. Systolic blood pressure, atrial fibrillation, and weight were additional predictors of symptomatic intracerebral hemorrhage. Current smokers had a lower rate of symptomatic intracerebral hemorrhage. Disability before current stroke (modified Rankin Score 2 to 5), diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers, and male sex were related to high mortality at 3 months. Conclusions— The adjusted outcomes from SITS-MOST were almost identical to those in relevant RCTs and reinforce the conclusion drawn previously in the unadjusted analysis. We identified several important outcome predictors to better identify patients suitable for thrombolysis.

Hematoma Growth and Outcome in Treated Neurocritical Care Patients With Intracerebral Hemorrhage Related to Oral Anticoagulant Therapy Comparison of Acute Treatment Strategies Using Vitamin K, Fresh Frozen Plasma, and Prothrombin Complex Concentrates

Background and Purpose— Intracerebral hemorrhage (ICH) is the most serious and potentially fatal complication of oral anticoagulant therapy (OAT). Still, there are no universally accepted treatment regimens for patients with OAT-ICH, and randomized controlled trials do not exist. The aim of the present study was to compare the acute treatment strategies of OAT-associated ICH using vitamin K (VAK), fresh frozen plasma (FFP), and prothrombin complex concentrates (PCCs) with regard to hematoma growth and outcome. Methods— In this retrospective study, a total of 55 treated patients were analyzed. Three groups were compared by reviewing the clinical, laboratory, and neuroradiological parameters: (1) patients who received PCCs alone or in combination with FFP or VAK (n=31), (2) patients treated with FFP alone or in combination with VAK (n=18), and (3) patients who received VAK as a monotherapy (n=6). The end points of early hematoma growth and outcome after 12 months were analyzed including multivariate analysis. Results— Hematoma growth within 24 hours occurred in 27% of patients. Incidence and extent of hematoma growth were significantly lower in patients receiving PCCs (19%/44%) compared with FFP (33%/54%) and VAK (50%/59%). However, this effect was no longer seen between PCC- and FFP-treated patients if international normalized ratio (INR) was completely reversed within 2 hours after admission. The overall outcome was poor (modified Rankin scale 4 to 6 in 77%). Predictors for hematoma growth were an increased INR after 2 hours, whereas administration of PCCs was significantly protective in multivariate analyses. Predictors for a poor outcome were age, baseline hematoma volume, and occurrence of hematoma growth. Conclusions— Overall, PCC was associated with a reduced incidence and extent of hematoma growth compared with FFP and VAK. This effect seems to be related to a more rapid INR reversal. Randomized controlled trials are needed to identify the most effective acute treatment regimen for lasting INR reversal because increased levels of INR were predisposing for hematoma enlargement.

MRI-Based and CT-Based Thrombolytic Therapy in Acute Stroke Within and Beyond Established Time Windows An Analysis of 1210 Patients

Background and Purpose— The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods— Five European stroke centers pooled the core data of their CT- and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT <3 hours, MRI <3 hours and >3 hours), and onset to treatment time as variables. Results— A total of 1210 patients were included (CT <3 hours: N=714; MRI <3 hours: N=316; MRI >3 hours: N=180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (P=0.66); 12, 13, and 14 points (P=0.019); and 130, 135, and 240 minutes (P<0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (P=0.213); mortality was 13.7%, 11.7%, and 13.3% (P=0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (P=0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, P=0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, P=0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard <3-hour CT-based treatment. Conclusion— Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis.

MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study

BACKGROUND Thrombolytic treatment with recombinant tissue plasminogen activator (rtPA) is approved for use within 3 h after stroke onset. Thus only a small percentage of patients can benefit. Meta-analyses and more recent studies suggest a benefit for a subset of patients beyond 3 h. We assessed the safety and efficacy of an MRI-based selection protocol for stroke treatment within and beyond 3 h compared with standard CT-based treatment. METHODS We assessed clinical outcome and incidence of symptomatic intracerebral haemorrhage (ICH) in 400 consecutive patients treated with intravenous rtPA. Patients eligible for thrombolysis within 3 h were selected by CT or MRI and beyond 3 h only by MRI. 18 patients were excluded from analysis because of violation of that algorithm. The remaining 382 patients were divided into three groups: CT-based treatment within 3 h (n=209); MRI-based treatment within 3 h (n=103); and MRI-based treatment beyond 3 h (n=70). FINDINGS Patients in group 3 (MRI > 3 h) had a similar 90 day outcome to those in the other two groups (48% were independent in the CT < or = 3 h group, 51% in the MRI < or = 3 h group, and 56% in group 3), but without an increased risk for symptomatic ICH (9%, 1%, 6%) or mortality (21%, 13%, 11%). MRI-selected patients overall had a significantly lower risk than CT-selected patients for symptomatic ICH (3% vs 9%; p=0.013) and mortality (12% vs 21%; p=0.021). Time to treatment did not affect outcomes in univariate and multivariate analyses. INTERPRETATION Our data suggest that beyond 3 h and maybe even within 3 h, patient selection is more important than time to treatment for a good outcome. Furthermore, MRI-based thrombolysis, irrespective of the time window, shows an improved safety profile while being at least as effective as standard CT-based treatment within 3 h.

IKK mediates ischemia-induced neuronal death

The IκB kinase complex IKK is a central component of the signaling cascade that controls NF-κB–dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.

Anticoagulant Reversal, Blood Pressure Levels, and Anticoagulant Resumption in Patients With Anticoagulation-Related Intracerebral Hemorrhage

IMPORTANCE Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH). OBJECTIVE To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption. EXPOSURES Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment. MAIN OUTCOMES AND MEASURES Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome. RESULTS Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%). CONCLUSIONS AND RELEVANCE Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01829581.

The synthetic cannabinoid Spice as a trigger for an acute exacerbation of cannabis induced recurrent psychotic episodes

It is established that cannabis consumption cannot only trigger transient psychotic episodes but also predisposes for the development of lasting paranoid schizophrenia in a dose dependent manner (Moore et al., 2007; Muller-Vahl and Emrich, 2008). Patients with a positive family history are at a higher risk for such drug induced schizophrenic disorders (Fergusson et al., 2006; Morgan and Curran, 2008). Crossreactions between different drugs to trigger recurrence of schizophrenic episodes are rare (Huffman et al., 2008). We present the case of a 25 year old man who had a history of cannabis induced recurrent psychotic episodes and an acute reactivation of symptoms after abuse of the synthetic cannabinoid “Spice”.

Two Tales: Hemorrhagic Transformation but Not Parenchymal Hemorrhage After Thrombolysis Is Related to Severity and Duration of Ischemia: MRI Study of Acute Stroke Patients Treated With Intravenous Tissue Plasminogen Activator Within 6 Hours

Background and Purpose— Intracerebral hemorrhage represents the most feared complication of treatment with intravenous tissue plasminogen activator. We studied whether perfusion-weighted imaging and diffusion-weighted imaging has the potential to identify patients at risk of severe intracerebral hemorrhage after treatment with intravenous tissue plasminogen activator. Methods— We analyzed data of prospectively studied MRI selected acute ischemic stroke patients treated with intravenous tissue plasminogen activator within 6 hours. All patients were examined by perfusion- and diffusion-weighted imaging ≤6 hours. Perfusion- and diffusion-weighted imaging lesion volumes were calculated. Hemorrhagic transformation was assessed on follow-up CT or MRI and diagnosed as hemorrhagic transformation, parenchymal hemorrhage, or symptomatic intracerebral hemorrhage according to ECASS II criteria. Results— Of 152 patients, hemorrhagic transformation was seen in 60 (39.5%), parenchymal hemorrhage in 15 (9.9%), and symptomatic intracerebral hemorrhage in 4 (2.6%). Multiple logistic regression analysis identified onset to treatment time after 3 to 6 hours (P<0.001), a larger perfusion-weighted imaging lesion volume (P=0.002), and, as a tendency, a higher score on the National Institutes of Health Stroke Scale on admission (P=0.068) as independent predictors of hemorrhagic transformation. Neither MRI lesion volumes nor severity of symptoms, but rather only an older age tended to be associated with parenchymal hemorrhage (P=0.087). Conclusion— Our results further support the concept of a different pathogenesis for hemorrhagic transformation and parenchymal hemorrhage. Whereas hemorrhagic transformation should be regarded as a clinically irrelevant epiphenomenon of ischemic damage and reperfusion, parenchymal hemorrhage appears to be related to biologic effects of tissue plasminogen activator and other pre-existing pathologic conditions, which deserve further investigation.

Prediction of malignant middle cerebral artery infarction by magnetic resonance imaging within 6 hours of symptom onset: A prospective multicenter observational study

Early identification of patients at risk of space‐occupying “malignant” middle cerebral artery (MCA) infarction (MMI) is needed to enable timely decision for potentially life‐saving treatment such as decompressive hemicraniectomy. We tested the hypothesis that acute stroke magnetic resonance imaging (MRI) predicts MMI within 6 hours of stroke onset.

Granulocyte Colony–Stimulating Factor in Patients With Acute Ischemic Stroke Results of the AX200 for Ischemic Stroke Trial

Background and Purpose— Granulocyte colony–stimulating factor (G-CSF; AX200; Filgrastim) is a stroke drug candidate with excellent preclinical evidence for efficacy. A previous phase IIa dose–escalation study suggested potential efficacy in humans. The present large phase IIb trial was powered to detect clinical efficacy in acute ischemic stroke patients. Methods— G-CSF (135 µg/kg body weight intravenous over 72 hours) was tested against placebo in 328 patients in a multinational, multicenter, randomized, and placebo-controlled trial (NCT00927836; www.clinicaltrial.gov). Main inclusion criteria were ⩽9-hour time window after stroke onset, infarct localization in the middle cerebral artery territory, baseline National Institutes of Health Stroke Scale score range of 6 to 22, and baseline diffusion-weighted imaging lesion size ≥15 mL. Primary and secondary end points were the modified Rankin scale score and the National Institutes of Health Stroke Scale score at day 90, respectively. Data were analyzed using a prespecified model that adjusted for age, National Institutes of Health Stroke Scale score at baseline, and initial infarct volume (diffusion-weighted imaging). Results— G-CSF treatment failed to meet the primary and secondary end points of the trial. For additional end points such as mortality, Barthel index, or infarct size at day 30, G-CSF did not show efficacy either. There was, however, a trend for reduced infarct growth in the G-CSF group. G-CSF showed the expected peripheral pharmacokinetic and pharmacodynamic profiles, with a strong increase in leukocytes and monocytes. In parallel, the cytokine profile showed a significant decrease of interleukin-1. Conclusions— G-CSF, a novel and promising drug candidate with a comprehensive preclinical and clinical package, did not provide any significant benefit with respect to either clinical outcome or imaging biomarkers. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.