Summary Background Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients ...in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. Methods We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70–99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT 00576693. Findings During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (–0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 26% of 224 patients vs 42 19% of 227 patients; p=0·0468) and major haemorrhage (29 13%of 224 patients vs 10 4% of 227 patients; p=0·0009). Interpretation The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. Funding National Institute of Neurological Disorders and Stroke (NINDS) and others.
Current recommendations do not specifically address the optimal blood pressure (BP) reduction for secondary stroke prevention in patients with previous cerebrovascular events. We conducted a ...systematic review and metaregression analysis on the association of BP reduction with recurrent stroke and cardiovascular events using data from randomized controlled clinical trials of secondary stroke prevention. For all reported events during each eligible study period, we calculated the corresponding risk ratios to express the comparison of event occurrence risk between patients randomized to antihypertensive treatment and those randomized to placebo. On the basis of the reported BP values, we performed univariate metaregression analyses according to the achieved BP values under the random-effects model (Method of Moments) for those adverse events reported in ≥10 total subgroups of included randomized controlled clinical trials. In pairwise meta-analyses, antihypertensive treatment lowered the risk for recurrent stroke (risk ratio, 0.73; 95% confidence interval, 0.62-0.87; P<0.001), disabling or fatal stroke (risk ratio, 0.71; 95% confidence interval, 0.59-0.85; P<0.001), and cardiovascular death (risk ratio, 0.85; 95% confidence interval, 0.75-0.96; P=0.01). In metaregression analyses, systolic BP reduction was linearly related to the lower risk of recurrent stroke (P=0.049), myocardial infarction (P=0.024), death from any cause (P=0.001), and cardiovascular death (P<0.001). Similarly, diastolic BP reduction was linearly related to a lower risk of recurrent stroke (P=0.026) and all-cause mortality (P=0.009). Funnel plot inspection and Egger statistical test revealed no evidence of publication bias. The extent of BP reduction is linearly associated with the magnitude of risk reduction in recurrent cerebrovascular and cardiovascular events. Strict and aggressive BP control seems to be essential for effective secondary stroke prevention.
To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for ...nonvalvular atrial fibrillation (NVAF).
We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta-analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH.
We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 ± 9.8 years, 57.8% men, median admission NIH Stroke Scale NIHSS
score 13 points, interquartile range 6-21). DOAC-related (n = 47) and VKA-related (n = 114) ICH did not differ in demographics, vascular risk factors, HAS-BLED and CHA
DS
-VASc scores, and antiplatelet pretreatment except for a higher prevalence of chronic kidney disease in VKA-related ICH. Patients with DOAC-related ICH had lower median NIHSS
scores (8 3-14 vs 15 7-25 points,
= 0.003), median baseline hematoma volume (12.8 4-40 vs 24.3 11-58.8 cm
,
= 0.007), and median ICH score (1 0-2 vs 2 1-3 points,
= 0.049). Severe ICH (>2 points) was less prevalent in DOAC-related ICH (17.0% vs 36.8%,
= 0.013). In multivariable analyses, DOAC-related ICH was independently associated with lower baseline hematoma volume (
= 0.006), lower NIHSS
scores (
= 0.022), and lower likelihood of severe ICH (odds ratio OR 0.34, 95% confidence interval CI 0.13-0.87,
= 0.025). In meta-analysis of eligible studies, DOAC-related ICH was associated with lower baseline hematoma volumes on admission CT (standardized mean difference = -0.57, 95% CI -1.02 to -0.12,
= 0.010) and lower in-hospital mortality rates (OR = 0.44, 95% CI 0.21-0.91,
= 0.030).
DOAC-related ICH is associated with smaller baseline hematoma volume and lesser neurologic deficit at hospital admission compared to VKA-related ICH.
Cerebral microbleeds (CMBs) have been established as an independent predictor of cerebral bleeding. There are contradictory data regarding the potential association of CMB burden with the risk of ...symptomatic intracerebral hemorrhage (sICH) in patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT).
To investigate the association of high CMB burden (>10 CMBs on a pre-IVT magnetic image resonance MRI scan) with the risk of sICH following IVT for AIS.
Eligible studies were identified by searching Medline and Scopus databases. No language or other restrictions were imposed. The literature search was conducted on October 7, 2015. This meta-analysis has adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) proposal.
Eligible prospective study protocols that reported sICH rates in patients with AIS who underwent MRI for CMB screening prior to IVT.
The reported rates of sICH complicating IVT in patients with AIS with pretreatment MRI were extracted independently for groups of patients with 0 CMBs (CMB absence), 1 or more CMBs (CMB presence), 1 to 10 CMBs (low to moderate CMB burden), and more than 10 CMBs (high CMB burden). An individual-patient data meta-analysis was also performed in the included studies that provided complete patient data sets.
Symptomatic intracerebral hemorrhage based on the European Cooperative Acute Stroke Study-II definition (any intracranial bleed with ≥4 points worsening on the National Institutes of Health Stroke Scale score).
We included 9 studies comprising 2479 patients with AIS. The risk of sICH after IVT was found to be higher in patients with evidence of CMB presence, compared with patients without CMBs (risk ratio RR, 2.36; 95% CI, 1.21-4.61; P = .01). A higher risk for sICH after IVT was detected in patients with high CMB burden (>10 CMBs) when compared with patients with 0 to 10 CMBs (RR, 12.10; 95% CI, 4.36-33.57; P < .001) or 1 to 10 CMBs (RR, 7.01; 95% CI, 3.20-15.38; P < .001) on pretreatment MRI. In the individual-patient data meta-analysis, high CMB burden was associated with increased likelihood of sICH before (unadjusted odds ratio, 31.06; 95% CI, 7.12-135.44; P < .001) and after (adjusted odds ratio, 18.17; 95% CI, 2.39-138.22; P = .005) adjusting for potential confounders.
Presence of CMB and high CMB burdens on pretreatment MRI were independently associated with sICH in patients with AIS treated with IVT. High CMB burden may be included in individual risk stratification scores predicting sICH risk following IVT for AIS.
Accumulating evidence from randomized controlled clinical trials suggests that tenecteplase may represent an effective treatment alternative to alteplase for acute ischemic stroke. In the present ...systematic review and meta-analysis, we sought to compare the efficacy and safety outcomes of intravenous tenecteplase to intravenous alteplase administration for acute ischemic stroke patients with large vessel occlusions (LVOs).
We searched MEDLINE (Medical Literature Analysis and Retrieval System Online) and Scopus for published randomized controlled clinical trials providing outcomes of acute ischemic stroke with confirmed LVO receiving intravenous thrombolysis with either tenecteplase at different doses or alteplase at a standard dose of 0.9 mg/kg. The primary outcome was the odds of modified Rankin Scale score of 0 to 2 at 3 months.
We included 4 randomized controlled clinical trials including a total of 433 patients. Patients with confirmed LVO receiving tenecteplase had higher odds of modified Rankin Scale scores of 0 to 2 (odds ratio, 2.06 95% CI, 1.15-3.69), successful recanalization (odds ratio, 3.05 95% CI, 1.73-5.40), and functional improvement defined as 1-point decrease across all modified Rankin Scale grades (common odds ratio, 1.84 95% CI, 1.18-2.87) at 3 months compared with patients with confirmed LVO receiving alteplase. There was little or no heterogeneity between the results provided from included studies regarding the aforementioned outcomes (I
≤20%). No difference in the outcomes of early neurological improvement, symptomatic intracranial hemorrhage, any intracranial hemorrhage, and the rates of modified Rankin Scale score 0 to 1 or all-cause mortality at 3 months was detected between patients with LVO receiving intravenous thrombolysis with either tenecteplase or alteplase.
Acute ischemic stroke patients with LVO receiving intravenous thrombolysis with tenecteplase have significantly better recanalization and clinical outcomes compared with patients receiving intravenous alteplase.
Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if ...a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke.
We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min sonothrombolysis; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility.
Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77–1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80–1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79–1·60; p=0·53).
Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care.
Cerevast Therapeutics.
Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency ...medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied.
In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients.
We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval CI, 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group.
In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).
Conflicting data exist on the safety and efficacy of IV thrombolysis (IVT) in patients with acute ischemic stroke (AIS) receiving dual antiplatelet pretreatment (DAPP). The aim of the present ...systematic review and meta-analysis is to assess the safety and outcome of DAPP history among patients with AIS treated with IVT.
We performed a comprehensive literature review to identify studies that investigated the safety and efficacy of DAPP among patients with AIS treated with IVT.
We identified 9 studies comprising 66,675 patients. In unadjusted analyses, DAPP was associated with a higher likelihood of pooled symptomatic intracranial hemorrhage (sICH; odds ratio OR 2.26; 95% confidence interval CI 1.39-3.67) and 3-month mortality (OR 1.47; 95% CI 1.25-1.73). DAPP was also related to higher odds of sICH according to Safe Implementation of Treatments in Stroke Monitoring Study (OR 2.71; 95% CI 2.05-3.59), European Cooperative Acute Stroke
II (OR 2.23; 95% CI 1.46-3.40), and National Institute of Neurological Disorders and Stroke (OR 1.59, 95% CI 1.38-1.83) definitions. There was no association between DAPP and 3-month favorable functional outcome (FFO, modified Rankin Scale mRS score 0-1) and 3-month functional independence (FI; mRS score 0-2). In adjusted analyses, history of DAPP was not associated with pooled sICH (OR 2.03; 95% CI 0.75-5.52), 3-month mortality (OR 1.11; 95% CI 0.87-1.40), 3-month FFO (OR 0.92; 95% CI 0.77-1.09), and 3-month FI (OR 1.01; 95% CI 0.89-1.15).
After adjustment for potential confounders, DAPP appears not to be associated with higher risk of adverse outcomes in patients with AIS treated with IVT.
Objective
The substantial clinical improvement in acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT), combined with the poor response of proximal intracranial occlusions ...to intravenous thrombolysis (IVT), led to questions regarding the utility of bridging therapy (BT; IVT followed by MT) compared to direct mechanical thrombectomy (dMT) for AIS patients with large vessel occlusion (LVO).
Methods
We aimed to investigate the comparative safety and efficacy of BT and dMT in AIS patients. We included all observational studies and post hoc analyses from randomized controlled clinical trials that provided data on the outcomes of AIS patients with LVO stratified by IVT treatment status prior to MT.
Results
We identified 38 eligible observational studies (11,798 LVO patients, mean age = 68 years, 56% treated with BT). In unadjusted analyses, BT was associated with a higher likelihood of 3‐month functional independence (odds ratio OR = 1.52, 95% confidence interval CI = 1.32–1.76), 3‐month functional improvement (common OR cOR for 1‐point decrease in modified Rankin Scale score = 1.52, 95% CI = 1.18–1.97), early neurological improvement (OR = 1.21, 95% CI = 1.83–1.76), successful recanalization (OR = 1.22, 95% CI = 1.02–1.46), and successful recanalization with ≤2 device passes (OR = 2.28, 95% CI = 1.43–3.64) compared to dMT. BT was also related to a lower likelihood of 3‐month mortality (OR = 0.64, 95% CI = 0.57–0.73). In the adjusted analyses, BT was independently associated with a higher likelihood of 3‐month functional independence (adjusted OR = 1.55, 95% CI = 1.26–1.91) and lower odds of 3‐month mortality (adjusted OR = 0.80, 95% CI = 0.66–0.97) compared to dMT. The two groups did not differ in functional improvement (adjusted cOR = 1.24, 95% CI = 0.89–1.74) or symptomatic intracranial hemorrhage (adjusted OR = 0.87, 95% CI = 0.61–1.25).
Interpretation
BT appears to be associated with improved functional independence without evidence for safety concerns, compared to dMT, for AIS patients with LVO. ANN NEUROL 2019;86:395–406
The objective of this study was to examine clinical outcomes and recanalization rates in a multicenter cohort of stroke patients receiving intravenous tissue plasminogen activator by site of ...occlusion localized with bedside transcranial Doppler. Angiographic studies with intraarterial thrombolysis suggest more proximal occlusions carry greater thrombus burden and benefit less from local therapy.
Using validated transcranial Doppler criteria for specific arterial occlusion (Thrombolysis in Brain Ischemia flow grades), we compared the rate of dramatic recovery (National Institutes of Health Stroke Scale score < or =2 at 24 hours) and favorable outcomes at 3 months (modified Rankin Scale < or =1) for each occlusion site. We determined the likelihood of recanalization at various occlusion sites and its predictors. Then, stepwise logistic regression was used to determine predictors of complete recanalization.
Three hundred thirty-five patients had a mean age 69+/-13 years and 48.5% were women (median baseline National Institutes of Health Stroke Scale score 16 range, 3 to 32, mean time to transcranial Doppler 140+/-84 minutes, and mean time to intravenous tissue plasminogen activator 145+/-68 minutes). Distal middle cerebral artery occlusion had an OR of 2 for complete recanalization (50 of 113 44.2%, 95% CI: 1.1 to 3.1, P=0.005), proximal middle cerebral artery 0.7 (49 of 163 30%, 95% CI: 0.4 to 1.1, P=0.13), terminal internal carotid artery 0.1 (one of 17 5.9%, 95% CI: 0.015 to 0.8, P=0.015), tandem cervical internal carotid artery/middle cerebral artery 0.7 (6 of 22 27%, 95% CI: 0.3 to 1.9, P=0.5), and basilar artery 0.96 (3 of 10 30%, 95% CI: 0.2 to 4, P=0.9). Prerecombinant tissue plasminogen activator National Institutes of Health Stroke Scale score, systolic blood pressure, glucose, and Thrombolysis in Brain Ischemia flow grade at the occlusion site were the negative independent predictors for complete recanalization in the final model. There were no associations among time to treatment, stroke mechanisms, or recanalization rate. Patients with no flow (Thrombolysis in Brain Ischemia 0) at the occlusion site had less probability of complete recanalization than patients with dampened flow (Thrombolysis in Brain Ischemia 3) (OR(adj): 0.256, 95% CI: 0.11 to 0.595, P=0.002). Continuous transcranial Doppler monitoring (exposure to ultrasound) was a positive predictor for complete recanalization (OR(adj): 3.02, 95% CI: 1.396 to 6.514, P=0.005). National Institutes of Health Stroke Scale score < or =2 at 24 hours was achieved in 66 of 305 patients (22%): distal middle cerebral artery 33% (35 of 107), tandem cervical internal carotid artery/middle cerebral artery 24% (5 of 21), proximal middle cerebral artery 16% (24 of 155), basilar artery 25% (2 of 8), and none of the patients with terminal internal carotid artery had dramatic recovery (0%, n=14; P=0.003). Modified Rankin Scale score < or =1 was achieved in 90 of 260 patients (35%): distal middle cerebral artery 52% (50 of 96), proximal middle cerebral artery 25% (33 of 131), tandem cervical internal carotid artery/middle cerebral artery 21% (3 of 14), terminal internal carotid artery 18% (2 of 11), and basilar artery 25% (2 of 8) (P<0.001). Patients with distal middle cerebral artery occlusion were twice as likely to have a good long-term outcome as patients with proximal middle cerebral artery (OR: 2.1, 95% CI: 1.1 to 4, P=0.025).
Clinical response to thrombolysis is influenced by the site of occlusion. Patients with no detectable residual flow signals as well as those with terminal internal carotid artery occlusions are least likely to respond early or long term.
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