Peter A. Ringleb

Guidelines for Management of Ischaemic Stroke and Transient Ischaemic Attack 2008

This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation.

30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.

BACKGROUND Carotid endarterectomy is effective in stroke prevention for patients with severe symptomatic carotid-artery stenosis, and carotid-artery stenting has been widely used as alternative treatment. Since equivalence or superiority has not been convincingly shown for either treatment, we aimed to compare the two. METHODS 1200 patients with symptomatic carotid-artery stenosis were randomly assigned within 180 days of transient ischaemic attack or moderate stroke (modified Rankin scale score of < or =3) carotid-artery stenting (n=605) or carotid endarterectomy (n=595). The primary endpoint of this hospital-based study was ipsilateral ischaemic stroke or death from time of randomisation to 30 days after the procedure. The non-inferiority margin was defined as less than 2.5% on the basis of an expected event rate of 5%. Analyses were on an intention-to-treat basis. This trial is registered at Current Controlled Trials with the international standard randomised controlled trial number ISRCTN57874028. FINDINGS 1183 patients were included in the analysis. The rate of death or ipsilateral ischaemic stroke from randomisation to 30 days after the procedure was 6.84% with carotid-artery stenting and 6.34% with carotid endarterectomy (absolute difference 0.51%, 90% CI -1.89% to 2.91%). The one-sided p value for non-inferiority is 0.09. INTERPRETATION SPACE failed to prove non-inferiority of carotid-artery stenting compared with carotid endarterectomy for the periprocedural complication rate. The results of this trial do not justify the widespread use in the short-term of carotid-artery stenting for treatment of carotid-artery stenoses. Results at 6-24 months are awaited.

Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study.

BACKGROUND Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). METHODS In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 microg/kg desmoteplase, 125 microg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. FINDINGS Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 microg/kg desmoteplase; 66 received 125 microg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 microg/kg desmoteplase, 36% (24 of 66) for 125 microg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 microg/kg desmoteplase 14.0% (0.5 cm(3)); 125 microg/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 microg/kg desmoteplase, 4.5% (3 of 66) for 125 microg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 microg/kg desmoteplase; 21% [14 of 66] for 125 microg/kg desmoteplase; and 6% [4 of 63] for placebo). INTERPRETATION The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. FUNDING PAION Deutschland GmbH; Forest Laboratories.

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia: Increased Risk of Hemorrhage With Combined Ultrasound and Tissue Plasminogen Activator: Results of a Phase II Clinical Trial

Background— Clinical studies using ultrasound at diagnostic frequencies in transcranial Doppler devices provided encouraging results in enhancing thrombolysis with tissue plasminogen activator (tPA) in acute stroke. Low-frequency ultrasound does not require complex positioning procedures, penetrates through the skull better, and has been demonstrated to accelerate thrombolysis with tPA in animal experiments in wide cerebrovascular territories without hemorrhagic side effects. We therefore conducted the first multicenter clinical trial to investigate safety of tPA plus low-frequency ultrasound (300 kHz). Methods— Acute stroke patients within a 6-hour time window were included (National Institutes of Health Stroke Scale scores >4). Magnetic resonance imaging (MRI) was used to document vascular occlusion and to rule out cerebral hemorrhage. Patients were allocated to combination therapy alternately; the first patient received tPA only, the second patient received tPA plus ultrasound, etc. Follow-up included serial MRI directly thereafter and 24 hours later to confirm recanalization and tissue imaging. Clinical recovery was measured after treatment and 3 months later. Results— 26 patients (70.4±9.7 years) entered the trial (12 tPA, 14 tPA plus ultrasound). The study was prematurely stopped because 5 of 12 patients from the tPA only group but 13 of 14 patients treated with the tPA plus ultrasound showed signs of bleeding in MRI (P<0.01). Within 3 days of treatment, 5 symptomatic hemorrhages occurred within the tPA plus ultrasound group. At 3 months, neither morbidity nor treatment-related mortality or recanalization rates differed between both groups. Conclusions— This study demonstrated bioeffects from low-frequency ultrasound that caused an increased rate of cerebral hemorrhages in patients concomitantly treated with intravenous tPA.

Short-term outcome after stenting versus endarterectomy for symptomatic carotid stenosis: a preplanned meta-analysis of individual patient data.

BACKGROUND Results from randomised controlled trials have shown a higher short-term risk of stroke associated with carotid stenting than with carotid endarterectomy for the treatment of symptomatic carotid stenosis. However, these trials were underpowered for investigation of whether carotid artery stenting might be a safe alternative to endarterectomy in specific patient subgroups. We therefore did a preplanned meta-analysis of individual patient data from three randomised controlled trials. METHODS Data from all 3433 patients with symptomatic carotid stenosis who were randomly assigned and analysed in the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial, the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) trial, and the International Carotid Stenting Study (ICSS) were pooled and analysed with fixed-effect binomial regression models adjusted for source trial. The primary outcome event was any stroke or death. The intention-to-treat (ITT) analysis included all patients and outcome events occurring between randomisation and 120 days thereafter. The per-protocol (PP) analysis was restricted to patients receiving the allocated treatment and events occurring within 30 days after treatment. FINDINGS In the first 120 days after randomisation (ITT analysis), any stroke or death occurred significantly more often in the carotid stenting group (153 [8·9%] of 1725) than in the carotid endarterectomy group (99 [5·8%] of 1708, risk ratio [RR] 1·53, [95% CI 1·20-1·95], p=0·0006; absolute risk difference 3·2 [1·4-4·9]). Of all subgroup variables assessed, only age significantly modified the treatment effect: in patients younger than 70 years (median age), the estimated 120-day risk of stroke or death was 50 (5·8%) of 869 patients in the carotid stenting group and 48 (5·7%) of 843 in the carotid endarterectomy group (RR 1·00 [0·68-1·47]); in patients 70 years or older, the estimated risk with carotid stenting was twice that with carotid endarterectomy (103 [12·0%] of 856 vs 51 [5·9%] of 865, 2·04 [1·48-2·82], interaction p=0·0053, p=0·0014 for trend). In the PP analysis, risk estimates of stroke or death within 30 days of treatment among patients younger than 70 years were 43 (5·1%) of 851 patients in the stenting group and 37 (4·5%) of 821 in the endarterectomy group (1·11 [0·73-1·71]); in patients 70 years or older, the estimates were 87 (10·5%) of 828 patients and 36 (4·4%) of 824, respectively (2·41 [1·65-3·51]; categorical interaction p=0·0078, trend interaction p=0·0013]. INTERPRETATION Stenting for symptomatic carotid stenosis should be avoided in older patients (age ≥70 years), but might be as safe as endarterectomy in younger patients. FUNDING The Stroke Association.

Superiority of Clopidogrel Versus Aspirin in Patients With Prior Cardiac Surgery

BackgroundAfter coronary artery bypass surgery, patients have a high cumulative rate of graft closure and recurrent ischemic events. We sought to determine whether antiplatelet therapy with clopidogrel would be more effective than aspirin, the accepted standard, in these patients. Methods and ResultsThe event rates for all-cause mortality, vascular death, myocardial infarction, stroke, and rehospitalization were determined for the 1480 patients with a history of cardiac surgery randomized to either clopidogrel or aspirin in a trial of 19 185 patients. The event rate per year of vascular death, myocardial infarction, stroke, or rehospitalization was 22.3% in the 705 patients randomized to aspirin and 15.9% in the 775 patients randomized to clopidogrel (P =0.001). A risk reduction was also seen in each of the individual end points examined, including a 42.8% relative risk reduction in vascular death in patients on clopidogrel versus aspirin (P =0.030). In a multivariate model incorporating baseline clinical characteristics, clopidogrel therapy was independently associated with a decrease in vascular death, myocardial infarction, stroke, or rehospitalization in patients with a history of cardiac surgery, with a 31.2% relative risk reduction (95% CI, 15.8 to 43.8;P =0.0003). Although clopidogrel therapy was efficacious in the entire Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) population, multivariate analysis demonstrated that patients with previous cardiac surgery derived particular benefit (P =0.015). ConclusionCompared with aspirin, clopidogrel therapy results in a striking reduction in the elevated risk for recurrent ischemic events seen in patients with a history of prior cardiac surgery, along with a decreased risk of bleeding.

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 ≤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 ≤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.

Stroke magnetic resonance imaging within 6 hours after onset of hyperacute cerebral ischemia.

We studied the diagnostic and prognostic value of diffusion‐ and perfusion‐weighted magnetic resonancce imaging (DWI and PWI) for the initial evaluation and follow‐up monitoring of patients with stroke that had ensued less than 6 hours previously. Further, we examined the role of vessel patency or occlusion and subsequent recanalization or persistent occlusion for further clinical and morphological stroke progression so as to define categories of patients and facilitate treatment decisions. Fifty‐one patients underwent stroke magnetic resonance imaging (DWI, PWI, magnetic resonance angiography, and T2‐weighted imaging) within 3.3 ± 1.29 hours, and, of those, 41 underwent follow‐up magnetic resonance imaging on day 2 and 28 on day 5. In addition, we assessed clinical scores (on the National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, Barthel Index, and Modified Rankin Scale) on days 1, 2, 5, 30, and 90 and performed volumetric analysis of lesion volumes. In all, 25 patients had a proximal, 18 a distal, and 8 no vessel occlusion. Furthermore, 15 of 43 patients exhibited recanalization on day 2. Vessel occlusion was associated with a PWI‐DWI mismatch on the initial magnetic resonance imaging, vessel patency with a PWI‐DWI match (p < 0.0001). Outcome scores and lesion volumes differed significantly between patients experiencing recanalization and those who did not (all p < 0.0001). Acute DWI and PWI lesion volumes correlated poorly with acute clinical scores and only modestly with outcome scores. We have concluded on the basis of this study that early recanalization saves tissue at risk of ischemic infarction and results in significantly smaller infarcts and a significantly better clinical outcome. Patients with proximal vessel occlusions have a larger amount of tissue at risk, a lower recanalization rate, and a worse outcome. Urgent recanalization seems to be of utmost importance for these patients. Ann Neurol 2001;49:460–469

Implementation and outcome of thrombolysis with alteplase 3–4·5 h after an acute stroke: an updated analysis from SITS-ISTR

BACKGROUND In September, 2008, the European Acute Stroke Study III (ECASS III) randomised trial and the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) observational study reported the efficacy and safety of the extension of the time window for intravenous alteplase treatment from within 3 h to within 4.5 h after stroke onset. We aimed to assess the implementation of the wider time window, its effect on the admission-to-treatment time, and safety and functional outcome in patients recorded in SITS-ISTR. METHODS Patients treated according to the criteria of the European Summary of Product Characteristics, except for the time window, were included. Patients were grouped according to whether they were registered into SITS-ISTR before or after October, 2008. We measured admission-to-treatment time and rates of symptomatic intracerebral haemorrhage, mortality, and functional independence at 3 months. FINDINGS 23 942 patients were included in SITS-ISTR between December, 2002, and February, 2010, of whom 2376 were treated 3-4.5 h after symptom onset. The proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs 67 of 1023 [7%]). The median admission-to-treatment time was 65 min both for patients registered before and after October, 2008 (p=0.94). 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2317 treated within 3-4.5 h of stroke had symptomatic intracerebral haemorrhage at 3 months (adjusted odds ratio [OR] 1.44, 95% CI 1.05-1.97; p=0.02). 2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3-4.5 h had died by the 3-month follow-up (adjusted OR 1.26, 95% CI 1.07-1.49; p=0.005); 10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3-4.5 h were functionally independent at 3 months (adjusted OR 0.84, 95% CI 0.75-0.95; p=0.005). INTERPRETATION Since October, 2008, thrombolysis within 3-4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier. Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset. FUNDING Boehringer Ingelheim, Ferrer, the European Union Public Health Executive Authority, and Medical Training and Research (ALF) from Stockholm County Council and Karolinska Institutet.