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.

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.

Focal cerebral ischemia induces changes in both MMP-13 and aggrecan around individual neurons.

INTRODUCTION: To test the hypothesis that matrix metalloprotease-13 (MMP-13) and aggrecan may play roles in post-ischemic neuronal pathophysiology, we examined the impact of middle cerebral artery occlusion/reperfusion (MCAO/R) on the abundance of these proteins in different regions of the infarct by immunohistochemistry (IHC) and Western blotting (WB). METHODS: The effect of MCAO/R on the abundance of MMP-13 and aggrecan was examined in 23 Wistar rats using antibodies against MMP-13 and aggrecan. BrdU was administered the last 2 days of the experiment. The cellular source of the respective antigens was examined with fluorescent double labeling using the neuronal marker NeuN. Sections were also stained for BrdU. The ischemic zone was defined by MRI on T2-weighted images and also on the tissue sections with the help of H and E counterstain. WB was performed for MMP-13. RESULTS: MMP-13 protein is highly induced in ischemic brain and is associated with neurons, whereas aggrecan is associated with the perineuronal matrix in non-ischemic brain. After 3 days of cerebral ischemia, the number of MMP-13 positive neurons in the periphery of the ischemic lesion increased compared to the respective area in the non-ischemic brain with a peak on day 7. A stronger staining for aggrecan was observed around MMP-13 positive neurons compared with other neurons. The majority of the MMP-13 positive neurons in normal non-ischemic brain were also NeuN positive. BrdU was incorporated into MMP-13 positive neurons in the periphery of the infarct. WB confirmed this results by detecting MMP-13 bands in ischemic brains and activated MMP-13 up to 14 days after ischemia. CONCLUSIONS: There is a close spatial association of MMP-13 and aggrecan around individual neurons. Both MMP-13 and aggrecan appear to be involved in perineuronal matrix remodeling suggesting a role in neuronal reorganization after cerebral ischemia.

Efficacy and costs of secondary prevention with antiplatelets after ischaemic stroke.

Ischaemic stroke and other atherothrombotic events substantially increase the medico-economic burden because of their high treatment costs and long-lasting disabilities with need for chronic care. Studies have shown that the cost of stroke represents approximately 3 - 5% of the annual health budget. Antiplatelet agents play a major role in secondary stroke prevention. Acetylsalicylic acid (ASA), ASA combined with extended-release dipyridamole (ER-Dip), and clopidogrel are all acceptable choices for first-line treatment in the secondary prevention of stroke. The newer antiplatelets, however, are more expensive than ASA, and their cost-effectiveness is not easily estimated. ASA has to be given to 33 stroke patients to prevent one future stroke, myocardial infarction (MI) or vascular death compared with placebo. Adding ER-Dip to ASA increases the benefit for the patients. A total of 33 stroke patients had to be treated with this combination, instead of ASA, to prevent one stroke. However, the combination of ASA plus ER-Dip does not prevent MI, vascular death or the combined end point of either stroke or death. Clopidogrel is more effective than ASA in preventing a combined end point of ischaemic stroke, MI, or vascular death, but it has not been shown to be superior to ASA in preventing recurrent stroke in transient ischaemic attack or stroke patients. Several subgroups, such as stroke patients with additional peripheral artery disease, patients with prior coronary artery bypass, patients with insulin-dependent diabetes, and patients with recurrent vascular events, were identified, in whom the benefit of clopidogrel is amplified. Taking economical aspects into account, the fixed combination of ASA and ER-Dip can be recommended for secondary stroke prevention as a first-line alternative to ASA in patients without major comorbidity. In patients with higher comorbidity, clopidogrel may be more effective for the individual patient compared with ASA, and might also be cost-effective. Furthermore, in patients with ASA intolerance clopidogrel is a useful, but expensive, alternative.