Symptomatic intracranial hemorrhage (sICH) is the most feared complication of intravenous thrombolytic therapy in acute ischemic stroke. Treatment of sICH is based on expert opinion and small case ...series, with the efficacy of such treatments not well established. This document aims to provide an overview of sICH with a focus on pathophysiology and treatment.
A literature review was performed for randomized trials, prospective and retrospective studies, opinion papers, case series, and case reports on the definitions, epidemiology, risk factors, pathophysiology, treatment, and outcome of sICH. The document sections were divided among writing group members who performed the literature review, summarized the literature, and provided suggestions on the diagnosis and treatment of patients with sICH caused by systemic thrombolysis with alteplase. Several drafts were circulated among writing group members until a consensus was achieved.
sICH is an uncommon but severe complication of systemic thrombolysis in acute ischemic stroke. Prompt diagnosis and early correction of the coagulopathy after alteplase have remained the mainstay of treatment. Further research is required to establish treatments aimed at maintaining integrity of the blood-brain barrier in acute ischemic stroke based on inhibition of the underlying biochemical processes.
Summary Background The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or ...severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial. Methods We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2–3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0–2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration. Findings Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 95% CI 0·77–0·94; adjusted relative risk 0·88 0·80–0·98). Interpretation Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials. Funding US National Institutes of Health and National Institute of Neurological Disorders and Stroke.
Summary Background Results of initial randomised trials of endovascular treatment for ischaemic stroke, published in 2013, were neutral but limited by the selection criteria used, early-generation ...devices with modest efficacy, non-consecutive enrolment, and treatment delays. Recent developments In the past year, six positive trials of endovascular thrombectomy for ischaemic stroke have provided level 1 evidence for improved patient outcome compared with standard care. In most patients, thrombectomy was performed in addition to thrombolysis with intravenous alteplase, but benefits were also reported in patients ineligible for alteplase treatment. Despite differences in the details of eligibility requirements, all these trials required proof of major vessel occlusion on non-invasive imaging and most used some imaging technique to exclude patients with a large area of irreversibly injured brain tissue. The results indicate that modern thrombectomy devices achieve faster and more complete reperfusion than do older devices, leading to improved clinical outcomes compared with intravenous alteplase alone. The number needed to treat to achieve one additional patient with independent functional outcome was in the range of 3·2–7·1 and, in most patients, was in addition to the substantial efficacy of intravenous alteplase. No major safety concerns were noted, with low rates of procedural complications and no increase in symptomatic intracerebral haemorrhage. Where next? Thrombectomy benefits patients across a range of ages and levels of clinical severity. A planned meta-analysis of individual patient data might clarify effects in under-represented subgroups, such as those with mild initial stroke severity or elderly patients. Imaging-based selection, used in some of the recent trials to exclude patients with large areas of irreversible brain injury, probably contributed to the proportion of patients with favourable outcomes. The challenge is how best to implement imaging in clinical practice to maximise benefit for the entire population and to avoid exclusion of patients with smaller yet clinically important potential to benefit. Although favourable imaging identifies patients who might benefit despite long delays from symptom onset to treatment, the proportion of patients with favourable imaging decreases with time. Health systems therefore need to be reorganised to deliver treatment as quickly as possible to maximise benefits. On the basis of available trial data, intravenous alteplase remains the initial treatment for all eligible patients within 4·5 h of stroke symptom onset. Those patients with major vessel occlusion should, in parallel, proceed to endovascular thrombectomy immediately rather than waiting for an assessment of response to alteplase, because minimising time to reperfusion is the ultimate aim of treatment.
Only 3% to 5% of patients with acute ischemic stroke receive intravenous recombinant tissue-type plasminogen activator (r-tPA) and <1% receive endovascular therapy. We describe access of the US ...population to all facilities that actually provide intravenous r-tPA or endovascular therapy for acute ischemic stroke.
We used US demographic data and intravenous r-tPA and endovascular therapy rates in the 2011 US Medicare Provider and Analysis Review data set. International Classification of Diseases-Ninth Revision codes 433.xx, 434.xx and 436 identified acute ischemic stroke cases. International Classification of Diseases-Ninth Revision code 99.10 defined intravenous r-tPA treatment and International Classification of Diseases-Ninth Revision code 39.74 defined endovascular therapy. We estimated ambulance response times using arc-Geographic Information System's network analyst and helicopter transport times using validated models. Population access to care was determined by summing the population contained within travel sheds that could reach capable hospitals within 60 and 120 minutes.
Of 370,351 acute ischemic stroke primary diagnosis discharges, 14,926 (4%) received intravenous r-tPA and 1889 (0.5%) had endovascular therapy. By ground, 81% of the US population had access to intravenous-capable hospitals within 60 minutes and 56% had access to endovascular-capable hospitals. By air, 97% had access to intravenous-capable hospitals within 60 minutes and 85% had access to endovascular hospitals. Within 120 minutes, 99% of the population had access to both intravenous and endovascular hospitals.
More than half of the US population has geographic access to hospitals that actually deliver acute stroke care but treatment rates remain low. These data provide a national perspective on acute stroke care and should inform the planning and optimization of stroke systems in the United States.
Thrombectomy, primarily with stent retrievers with or without adjunctive aspiration, provided clinical benefit across multiple prospective randomized trials. Whether this benefit is exclusive to ...stent retrievers is unclear.
THERAPY (The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke; NCT01429350) was an international, multicenter, prospective, randomized (1:1), open label, blinded end point evaluation, concurrent controlled clinical trial of aspiration thrombectomy after intravenous alteplase (IAT) administration compared with intravenous-alteplase alone in patients with large vessel ischemic stroke because of a thrombus length of ≥8 mm. The primary efficacy end point was the percent of patients achieving independence at 90 days (modified Rankin Scale score, 0-2; intention-to-treat analysis). The primary safety end point was the rate of severe adverse events (SAEs) by 90 days (as treated analysis). Patients were randomized 1:1 across 36 centers in 2 countries (United States and Germany).
Enrollment was halted after 108 (55 IAT and 53 intravenous) patients (of 692 planned) because of external evidence of the added benefit of endovascular therapy to intravenous-alteplase alone. Functional independence was achieved in 38% IAT and 30% intravenous intention-to-treat groups (P=0.52). Intention-to-treat ordinal modified Rankin Scale odds ratio was 1.76 (95% confidence interval, 0.86-3.59; P=0.12) in favor of IAT. Secondary efficacy analyses all demonstrated a consistent direction of effect toward benefit of IAT. No differences in symptomatic intracranial hemorrhage rates (9.3% IAT versus 9.7% intravenous, P=1.0) or 90-day mortality (IAT: 12% versus intravenous: 23.9%, P=0.18) were observed.
THERAPY did not achieve its primary end point in this underpowered sample. Directions of effect for all prespecified outcomes were both internally and externally consistent toward benefit. It is possible that an alternate method of thrombectomy, primary aspiration, will benefit selected patients harboring large vessel occlusions. Further study on this topic is indicated.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01429350.
Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a ...combined approach is more effective than intravenous t-PA alone is uncertain.
We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability).
The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval CI, -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale NIHSS score 8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83).
The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).
...by the 1990s, randomised trials showed that the reduction in the risk of recurrent ischaemic stroke by intravenous heparin was negated by an increase in the risk of intracranial haemorrhage within ...the first 2 weeks—the highest risk period for recurrence.1 Use of aspirin starting within 48 h of stroke became the standard of care, and in the 2000s, dual antiplatelet therapy (adding a second antiplatelet drug to aspirin) showed benefit when limited to the first 21–30 days from onset of mild ischaemic stroke or high-risk transient ischaemic attack.2 In the meantime, long-term anticoagulation with warfarin became the mainstay for cardioembolic subtypes of stroke, such as in people with atrial fibrillation.2 More recently, direct oral anticoagulants have been shown to reduce the risk of haemorrhage compared with warfarin for preventive treatment after cardioembolic stroke, but with similar efficacy, prompting re-evaluation of anticoagulation strategies in people at lower risk of stroke recurrence than those with atrial fibrillation. ...the phase 3 COMPASS trial showed a significant benefit of a direct oral anticoagulant (low-dose rivaroxaban) added to aspirin to prevent recurrent ischaemia in patients with stable coronary or peripheral vascular atherosclerosis, including in the 5% of participants who had remote ischaemic stroke (median 5·3 years before enrolment).3 The benefit of earlier initiation of this regimen, during the highest risk and reward period after ischaemic stroke, in patients with atherosclerotic stroke remains to be seen. The PACIFIC-Stroke trialists5 recently reported remarkably similar results for another factor XIa inhibitor, asundexian, with a similar dose-finding study design, in a similar patient population, and with the same composite primary endpoint, including covert brain infarcts.
...directions of effect favoured intravenous thrombolysis use; in SWIFT-DIRECT,9 90-day functional independence was observed in 57% of the randomly assigned participants in the endovascular therapy ...group versus 65% in the intravenous thrombolysis and endovascular therapy group, and 55% versus 61% in DIRECT-SAFE.10 Furthermore, symptomatic intracerebral haemorrhage rates were similar between the treatment groups of each trial, and angiographic reperfusion rates were nominally higher in the intravenous thrombolysis-randomised group of the SWIFT-DIRECT trial. ...intravenous thrombolysis might be the only reperfusion therapy received if intracranial thrombi prove inaccessible due to vessel tortuosity or resistant to thrombectomy attempts. ...residual thrombi that are too distal for thrombectomy, and even non-visualised microthrombi, might be recanalised by systemic thrombolysis.12 Finally, intravenous thrombolysis might improve the rate of technically successful thrombectomy.8 Most benefits would be amplified when the time gap between intravenous thrombolysis and endovascular therapy is larger, as in the more common scenario when patients receive intravenous thrombolysis at outlying hospitals before transfer to an endovascular-capable hospital.
Enlarged perivascular spaces (EPVS), specifically in stroke patients, has been shown to strongly correlate with other measures of small vessel disease and cognitive impairment at 1 year follow-up. ...Typical grading of EPVS is often challenging and time consuming and is usually based on a subjective visual rating scale. The purpose of the current study was to develop an interpretable, 3D neural network for grading enlarged perivascular spaces (EPVS) severity at the level of the basal ganglia using clinical-grade imaging in a heterogenous acute stroke cohort, in the context of total cerebral small vessel disease (CSVD) burden. T2-weighted images from a retrospective cohort of 262 acute stroke patients, collected in 2015 from 5 regional medical centers, were used for analyses. Patients were given a label of 0 for none-to-mild EPVS (< 10) and 1 for moderate-to-severe EPVS (≥ 10). A three-dimensional residual network of 152 layers (3D-ResNet-152) was created to predict EPVS severity and 3D gradient class activation mapping (3DGradCAM) was used for visual interpretation of results. Our model achieved an accuracy 0.897 and area-under-the-curve of 0.879 on a hold-out test set of 15% of the total cohort (n = 39). 3DGradCAM showed areas of focus that were in physiologically valid locations, including other prevalent areas for EPVS. These maps also suggested that distribution of class activation values is indicative of the confidence in the model's decision. Potential clinical implications of our results include: (1) support for feasibility of automated of EPVS scoring using clinical-grade neuroimaging data, potentially alleviating rater subjectivity and improving confidence of visual rating scales, and (2) demonstration that explainable models are critical for clinical translation.
Endovascular strategies provide unique opportunity to correlate angiographic measures of collateral circulation at the time of endovascular therapy. We conducted systematic analyses of collaterals at ...conventional angiography on recanalization, reperfusion, and clinical outcomes in the endovascular treatment arm of the Interventional Management of Stroke (IMS) III trial.
Prospective evaluation of angiographic collaterals was conducted via central review of subjects treated with endovascular therapy in IMS III (n=331). Collateral grade before endovascular therapy was assessed with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale, blinded to all other data. Statistical analyses investigated the association between collaterals with baseline clinical variables, angiographic measures of recanalization, reperfusion and clinical outcomes.
Adequate views of collateral circulation to the ischemic territory were available in 276 of 331 (83%) subjects. Collateral grade was strongly related to both recanalization of the occluded arterial segment (P=0.0016) and downstream reperfusion (P<0.0001). Multivariable analyses confirmed that robust angiographic collateral grade was a significant predictor of good clinical outcome (modified Rankin Scale score≤2) at 90 days (P=0.0353), adjusted for age, history of diabetes mellitus, National Institutes of Health Stroke Scale strata, and Alberta Stroke Program Early CT Score. The relationship between collateral flow and clinical outcome may depend on the degree of reperfusion.
More robust collateral grade was associated with better recanalization, reperfusion, and subsequent better clinical outcomes. These data, from the largest endovascular trial to date, suggest that collaterals are an important consideration in future trial design.
http://www.clinicaltrials.gov. Unique identifier: NCT00359424.
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