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Werner Hacke

Publications and source records attributed to Werner Hacke.

At least 19 recordsLinked to original sources
PubMed2006

Can multivariable risk-benefit profiling be used to select treatment-favorable patients for thrombolysis in stroke in the 3- to 6-hour time window?

BACKGROUND AND PURPOSE: The Stroke-Thrombolytic Predictive Instrument (Stroke-TPI) uses multivariate equations to predict outcomes with and without thrombolysis. We sought to examine whether such a multivariate predictive instrument might be useful in selecting patients with a favorable risk-benefit treatment profile for therapy after 3 hours. METHODS: We explored outcomes in patients from 5 major randomized clinical trials testing intravenous recombinant tissue plasminogen activator (rt-PA) classified by the Stroke-TPI as "treatment-favorable" or "treatment-unfavorable." We used iterative bootstrap re-sampling to estimate how such a model would perform on independent test data. RESULTS: Among patients treated within the 3- to 6-hour window, 67% of patients were classified by Stroke-TPI predicted outcomes as "treatment-favorable" and 33% were classified as "treatment-unfavorable." Outcomes in the treatment-favorable group demonstrated benefit for thrombolysis (modified Rankin Scale score < or =1: 44.0% with rt-PA versus 34.2 with placebo, P=0.005), whereas harm was demonstrated in the treatment-unfavorable group (modified Rankin Scale score < or =1: 31.3% with rt-PA versus 38.3% with placebo; P=0.004). Bootstrap resampling with complete cross-validation showed that the absolute margin of benefit in the treatment-favorable group diminished on average by 36% between derivation and independent validation sets, but still represented a significant tripling of improvement in benefit compared with conventional inclusion criteria (5.2% [interquartile range, 1.7% to 8.6%] versus 1.8% [interquartile range, -0.5 to 4.1], P<0.0001). CONCLUSIONS: Such multivariable risk-benefit profiling may be useful in the selection of acute stroke patients for rt-PA therapy even more than 3 hours after symptom onset. Prospective testing is indicated.

Aged↗
PubMed2006

The stroke-thrombolytic predictive instrument: a predictive instrument for intravenous thrombolysis in acute ischemic stroke.

BACKGROUND AND PURPOSE: Many patients with ischemic stroke eligible for recombinant tissue plasminogen activator (rt-PA) are not treated in part because of the risks and benefits perceived by treating physicians. Therefore, we aimed to develop a Stroke-Thrombolytic Predictive Instrument (TPI) to aid physicians considering thrombolysis for stroke. METHODS: Using data from 5 major randomized clinical trials (n=2184) testing rt-PA in the 0- to 6-hour window, we developed logistic regression equations using clinical variables as potential predictors of a good outcome (modified Rankin Scale score < or =1) and of a catastrophic outcome (modified Rankin Scale score > or =5), with and without rt-PA. The models were internally validated using bootstrap re-sampling. RESULTS: To predict good outcome, in addition to rt-PA treatment, 7 variables significantly affected prognosis and/or the treatment-effect of rt-PA: age, diabetes, stroke severity, sex, previous stroke, systolic blood pressure, and time from symptom onset. To predict catastrophic outcome, only age, stroke severity, and serum glucose were significant; rt-PA treatment was not. For patients treated within 3 hours, the median predicted probability of a good outcome with rt-PA was 42.9% (interquartile range [IQR]=18.6% to 64.7%) versus 25.3% (IQR=9.8% to 46.2%) without rt-PA; the median predicted absolute benefit was 12.5% (IQR=5.1% to 21.0%). The median probability for a catastrophic outcome, with or without, rt-PA was 15.2% (IQR=8.0% to 31.2%). The area under the receiver-operator characteristic curve was 0.788 for the model predicting good outcome and 0.775 for the model predicting bad outcome. CONCLUSIONS: The Stroke-TPI predicts good and bad functional outcomes with and without thrombolysis. Incorporated into a usable tool, it may assist in decision-making.

Aged↗
PubMed2006

Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee.

This article represents the recommendations for the management of spontaneous intracerebral haemorrhage of the European Stroke Initiative (EUSI). These recommendations are endorsed by the 3 European societies which are represented in the EUSI: the European Stroke Council, the European Neurological Society and the European Federation of Neurological Societies.

Emergency Medical Services↗
PubMed2006

Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset.

BACKGROUND AND PURPOSE: Desmoteplase is a novel plasminogen activator with favorable features in vitro compared with available agents. This study evaluated safety and efficacy of intravenous (IV) desmoteplase in patients with perfusion/diffusion mismatch on MRI 3 to 9 hours after onset of acute ischemic stroke. METHODS: DEDAS was a placebo-controlled, double-blind, randomized, dose-escalation study investigating doses of 90 microg/kg and 125 microg/kg desmoteplase. Eligibility criteria included baseline National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch. The safety end point was the rate of symptomatic intracranial hemorrhage. Primary efficacy co-end points were MRI reperfusion 4 to 8 hours after treatment and good clinical outcome at 90 days. The primary analyses were intent-to-treat. Before unblinding, a target population, excluding patients violating specific MRI criteria, was defined. RESULTS: Thirty-seven patients were randomized and received treatment (intent-to-treat; placebo: n=8; 90 microg/kg: n=14; 125 microg/kg: n=15). No symptomatic intracranial hemorrhage occurred. Reperfusion was achieved in 37.5% (95% CI [8.5; 75.5]) of placebo patients, 18.2% (2.3; 51.8) of patients treated with 90 microg/kg desmoteplase, and 53.3% (26.6; 78.7) of patients treated with 125 microg/kg desmoteplase. Good clinical outcome at 90 days occurred in 25.0% (3.2; 65.1) treated with placebo, 28.6% (8.4; 58.1) treated with 90 microg/kg desmoteplase and 60.0% (32.3; 83.7) treated with 125 microg/kg desmoteplase. In the target population (n=25), the difference compared with placebo increased and was statistically significant for good clinical outcome with 125 microg/kg desmoteplase (P=0.022). CONCLUSIONS: Treatment with IV desmoteplase 3 to 9 hours after ischemic stroke onset appears safe. At a dose of 125 microg/kg desmoteplase appeared to improve clinical outcome, especially in patients fulfilling all MRI criteria. The results of DEDAS generally support the results of its predecessor study, Desmoteplase in Acute Ischemic Stroke (DIAS).

Adult↗
PubMed2006

Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.

BACKGROUND: Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. METHODS: We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. RESULTS: The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046). CONCLUSIONS: In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.).

Adult↗
PubMed2006

Outcome and symptomatic bleeding complications of intravenous thrombolysis within 6 hours in MRI-selected stroke patients: comparison of a German multicenter study with the pooled data of ATLANTIS, ECASS, and NINDS tPA trials.

BACKGROUND AND PURPOSE: We compared outcome and symptomatic bleeding complications of intravenous tissue plasminogen activator (IV-tPA) within 6 hours of symptom onset in MRI-selected patients with acute middle cerebral artery infarction with the pooled data of the large stroke tPA trials. METHODS: Patients were examined by perfusion-weighted and diffusion-weighted imaging < or =6 hours. Within 3 hours, patients were treated according to Second European-Australasian Acute Stroke Study (ECASS II) criteria. After 3 to 6 hours, treatment with IV-tPA was performed based on MRI findings. Favorable outcome was assessed after 90 days using a dichotomized modified Rankin scale score of 0 to 1. Intracerebral bleeding complications were assessed on follow-up MRI or computed tomography. Data were compared with the pooled placebo and pooled tPA patients of the ATLANTIS, ECASS, and National Institute of Neurological Disorders and Stroke (NINDS) tPA trials. RESULTS: From 174 MRI-selected tPA patients, 62% (n=108) were treated in < or =3 hours and 38% (n=66) after 3 to 6 hours. Favorable outcome was more frequent in MRI-selected tPA patients (48% [95% CI, 39 to 54]) compared with pooled placebo (33% [95% CI, 31 to 36]; P<0.001) and pooled tPA patients (40% [95% CI, 37 to 42]; P=0.046). Odds ratios for favorable outcome in the MRI-selected tPA group were 1.82 (1.32 to 2.51) compared with the pooled placebo and 1.39 (1.01 to 1.92) compared with the pooled tPA group. The rate of symptomatic intracerebral hemorrhage in MRI-selected tPA patients (3% [95% CI, 0 to 5]) was lower than in the pooled tPA group (8% [95% CI, 7 to 10]; P=0.012) and comparable to the pooled placebo group (2% [95% CI, 1 to 3]; P=0.392). CONCLUSIONS: This study supports that it is safe and effective to expand the time window for IV-tPA up to 6 hours in patients with tissue at risk as defined by MRI.

Adolescent↗
PubMed2006

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.

Aged↗
PubMed2005

Prolonged low-dose intravenous thrombolysis in a stroke patient with distal basilar thrombus.

BACKGROUND AND PURPOSE: Patients with high-grade basilar artery stenosis secondary to thromboembolism are at high risk of developing subsequent vessel occlusion. Optimal medical management of this condition is unclear. SUMMARY OF CASE: We present a patient with a small subacute brain stem infarction and filiform distal basilar residual lumen attributable to arterioarterial or cardiogenic embolism. Beginning 3 days after symptom onset, low-dose intravenous thrombolysis with 0.125 mg/kg recombinant tissue plasminogen activator was continuously infused for 48 hours. Follow-up magnetic resonance angiography revealed complete resolution of the embolus. No further cerebral ischemic episodes occurred during 3-month follow-up, and the basilar artery remained patent. CONCLUSIONS: Our observation suggests a potential for prolonged low-dose intravenous thrombolysis in basilar artery embolism, but further data are needed to judge the effectiveness and risk of this intervention.

Aged↗
PubMed2005

A global view of atherothrombosis: baseline characteristics in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.

BACKGROUND: The manifestations of atherothrombosis such as myocardial infarction, ischemic stroke, limb ischemia, or cardiovascular death pose a global health care burden. Additional therapies to decrease ischemic events in patients with established vascular disease or at risk for developing vascular disease are necessary. We sought to characterize the risk factors and treatments of a diverse contemporary population of patients with atherothrombosis. METHODS: The CHARISMA trial has enrolled 15,603 patients from around the world. Patients with established coronary, cerebrovascular, or peripheral arterial disease, or those at high risk of developing atherothrombosis due to multiple risk factors, have been randomized to receive either the adenosine diphosphate receptor antagonist clopidogrel or placebo, in addition to background therapy with low- to moderate-dose aspirin. RESULTS: A high percentage of enrolled patients are being treated with statins and angiotensin-converting enzyme inhibitors. In the CHARISMA population, a total of 75.6% of the population had an abnormal body mass index: 42.2% were overweight and 33.4% were obese, with particularly high rates in the United States, especially of morbid obesity. Correspondingly, the prevalence of diabetes was 42%. CONCLUSION: The CHARISMA trial will further characterize atherothrombosis and provide insight into the role of dual antiplatelet therapy in improving outcomes in patients with multiple risk factors or established vascular disease. Of note, the rates of obesity and diabetes in patients with atherothrombosis throughout the world are particularly alarming.

Adult↗
PubMed2004

The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase.

BACKGROUND AND PURPOSE: Most acute ischemic stroke patients arrive after the 3-hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose-finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI. METHODS: DIAS was a placebo-controlled, double-blind, randomized, dose-finding phase II trial. Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight-adjusted doses escalating through 62.5 microg/kg, 90 microg/kg, and 125 microg/kg were subsequently investigated in 57 patients (referred to as Part 2). The safety endpoint was the rate of sICH. Efficacy endpoints were the rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days. RESULTS: Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7%). In Part 2, the sICH rate was 2.2%. No sICH occurred with placebo in either part. Reperfusion rates up to 71.4% (P=0.0012) were observed with desmoteplase (125 microg/kg) compared with 19.2% with placebo. Favorable 90-day clinical outcome was found in 22.2% of placebo-treated patients and between 13.3% (62.5 microg/kg; P=0.757) and 60.0% (125 microg/kg; P=0.0090) of desmoteplase-treated patients. Early reperfusion correlated favorably with clinical outcome (P=0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6% of patients without reperfusion. CONCLUSIONS: Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion/diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 microg/kg.

Acute Disease↗
PubMed2004

Increased presence of matrix metalloproteinases 2 and 9 in short- and long-term experimental herpes simplex virus encephalitis.

Herpes simplex virus encephalitis (HSVE) causes elevated morbidity and mortality despite antiviral treatment. Virus-independent mechanisms may perpetuate brain damage. Matrix metalloproteinases (MMPs) target extracellular matrix components. This study describes the protein and mRNA expression of MMP2 and MMP9 in experimental HSVE in the short and long term. Ten SJL-NBOM mice were infected with neurovirulent HSV-1 and compared with nine controls. The presence of MMP2 and MMP9 in brain tissue was analyzed with sodium-dodecyl-sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) gelatin zymography and mRNA expression of MMP2 and MMP9 with quantitative real-time PCR at days 7, 21 and 180 post-inoculation. Infected animals had a significantly elevated gelatinolytic activity of MMP2 at all time points, and of MMP9 at days 21 and 180. Increased presence of MMP2 and MMP9 in chronic HSVE may contribute to ongoing damage. Inhibition of MMP2 and MMP9 might be a suitable target for therapeutic intervention.

Animals↗
PubMed2004

Measuring outcomes as a function of baseline severity of ischemic stroke.

BACKGROUND: The spectrum of neurological impairments following acute ischemic stroke is broad. The initial stroke severity predicts responses to treatment and outcomes after ischemic stroke. While clinical trials are using baseline severity as an enrollment criterion or a stratified variable, adjustment of outcome measures as a function of initial impairments has not been done. METHODS: We developed a responder analysis that defines favorable outcomes at 90 days as influenced by the baseline National Institutes of Health Stroke Scale (NIHSS). Favorable outcome was defined as a modified Rankin Scale (mRS) score of 0 if the baseline NIHSS score was <8, mRS score of 0-1 if the NIHSS score was 8-14, and mRS score of 0-2 if the NIHSS score was >14. The concept stemmed from the data of two European rtPA trials. The analysis is a predefined secondary endpoint in a trial testing abciximab. We also used the analysis to reexamine the Trial of Org 10172 in Acute Stroke Treatment data. RESULTS: The responder analysis did not change the overall results of any of the 3 previous trials, but it did give information about differences in responses among subgroups of patients. Evidence about the potential utility of tPA for treatment of patients with mild stroke appeared from the analysis of the second European trial of rtPA. The analysis also provided a hint of efficacy of abciximab. CONCLUSIONS: The responder analysis appears to be a potentially useful way to evaluate outcomes of patients enrolled in clinical trials in stroke. The results of the analysis have clinical relevance and can further explain differences in responses to therapies. In addition, the analysis allows for improved comparisons of results among clinical trials.

Acute Disease↗
PubMed2004

Carotid artery stenting:the need for randomised trials.

Endovascular treatment for carotid artery stenosis avoids some of the complications of carotid endarterectomy, but has not been widely accepted. Concerns about the risks and benefits of endovascular treatment led to the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS). There was no difference in major outcome events between endovascular treatment and carotid endarterectomy, but the rate of procedural stroke or death was higher than desirable. There was no difference either in the rate of stroke during follow-up, but the confidence intervals were very wide and severe ipsilateral carotid stenosis was more frequent 1 year after endovascular treatment than after carotid surgery. Two other randomised trials of carotid stenting were stopped early after poor outcomes in stented patients. These early trials used techniques which have now been superseded, but the results emphasise the need to improve the safety of endovascular treatment. Recent advances designed to improve safety include new designs of stents and delivery systems, and devices designed to protect the brain from embolisation during stenting. However, there is little convincing evidence that these new devices reduce the rate of stroke. Moreover, a systematic review of the existing randomised trial data concluded that there the current evidence does not support a shift away from recommending carotid endarterectomy as the standard treatment for carotid stenosis. There is therefore a clear need for further randomised trials of carotid stenting. Three of the ongoing trials, EVA-3S, SPACE and ICSS (CAVATAS-2), have prospectively agreed to combine individual patient data after completion of follow-up. This meta-analysis will provide results similar to a mega-trial and should also allow informative subgroup analyses. The co-operation between the trials in agreeing to perform this meta-analysis is a major advance in trial design. The result should determine whether carotid stenting truly rivals carotid endarterectomy as the treatment of choice for carotid stenosis.

Carotid Stenosis↗
PubMed2004

Leukocyte count as an independent predictor of recurrent ischemic events.

BACKGROUND AND PURPOSE: Inflammatory markers predict first-time ischemic events. We investigated whether leukocyte and differential counts predict recurrent events and ischemic events in high-risk populations, and whether such events are preceded by acutely exacerbated inflammation. METHODS: We studied 18 558 patients with ischemic stroke, myocardial infarction, or peripheral arterial disease who participated in the trial of Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE), a study that compared the occurrence of ischemic stroke, myocardial infarction, or vascular death under randomized treatment with aspirin or clopidogrel. Leukocyte counts were frequently assessed during followup. RESULTS: Compared with the quartile with lowest leukocyte counts at baseline (<5.9x10(9)/L), patients in the top quartile (>8.2x10(9)/L) had higher risks for ischemic stroke (relative risk 1.30; P=0.007), myocardial infarction (relative risk 1.56, P<0.001), and vascular death (relative risk 1.51; P<0.001) after adjustment for other risk factors. Neutrophil counts contributed most to increased risk. Assessments of regression dilution effects based on replicate measurements show that these risk associations may underestimate the real associations by 30 to 50%. Treatment with aspirin or clopidogrel did not influence predictive effects by leukocytes. In the week before a recurrent event, but not at earlier time points, the leukocyte count was significantly increased over baseline levels (n=211; mean difference +0.46x10(9)/L; P=0.005). CONCLUSIONS: Leukocyte counts and mainly neutrophil counts are independently associated with ischemic events in these high-risk populations. An increase of leukocyte counts over baseline levels heralds a period of increased risk lasting about one week.

Aspirin↗