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IV TPA studies
Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS)
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, et al
.JAMA. 1995 Oct 4;274(13):1017-25.Department of Neurology, University of Heidelberg, Germany
- To evaluate the efficacy and safety of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke.Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial.A total of 75 hospitals in 14 European countries.A total of 620 patients with acute ischemic hemispheric stroke and moderate to severe neurologic deficit and without major early infarct signs on initial computed tomography (CT).Patients were randomized to treatment with 1.1 mg per kilogram of body weight of rt-PA (alteplase) or placebo within 6 hours from the onset of symptoms.OUTCOME MEASURES:Primary end points included Barthel Index (BI) and modified Rankin Scale (RS) at 90 days. Secondary end points included combined BI and RS, Scandinavian Stroke Scale (SSS) at 90 days, and 30-day mortality. Tertiary end points included early neurologic recovery (SSS) and duration of in-hospital stay. Safety parameters included mortality and incidence of intracranial or extracranial hemorrhage.
- RESULTS:A total of 109 patients (17.4%) were included in the trial despite major protocol violations but excluded from the TP. There was no difference in the primary end points in the ITT analysis, while the TP analysis revealed a significant difference in the RS in favor of rt-PA-treated patients (P = .035). Of the secondary end points, the combined BI and RS showed a difference in favor of rt-PA-treated patients in both analyses (P < .001). Neurologic recovery at 90 days was significantly better for rt-PA-treated patients in the TP (P = .03). The speed of neurologic recovery assessed by the SSS was significantly better up to 7 days in the ITT analysis and up to 30 days for the TP in the rt-PA treatment arm. In-hospital stay was significantly shorter in the rt-PA treatment arm in both analyses. There were no statistically significant differences in the mortality rate at 30 days or in the overall incidence of intracerebral hemorrhages among the rt-PA and placebo treatment arms in either analysis. However, the occurrence of large parenchymal hemorrhages was significantly more frequent in the rt-PA-treated patients.
- CONCLUSIONS:Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. However, the identification of this subgroup is difficult and depends on recognition of early major CT signs of early infarction. Therefore, since treating ineligible patients is associated with an unacceptable increase of hemorrhagic complications and death, intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients.
- Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II).
- Second European-Australasian Acute Stroke Study Investigators.Lancet. 1998 Oct 17;352(9136):1245-51.Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P.Department of Neurology, University of Heidelberg, Germany. firstname.lastname@example.org
- We have assessed the safety and efficacy of intravenous thrombolysis with alteplase (0.9 mg/kg bodyweight) within 6 h ofstroke onset.
- METHODS:This non-angiographic, randomised, double-blind, trial enrolled 800 patients in Europe, Australia, and New Zealand. Alteplase (n=409) and placebo (n=391) were randomly assigned with stratification for time since symptom onset (0-3 h or 3-6 h). The primary endpoint was the modified Rankin scale (mRS) at 90 days, dichotomised for favourable (score 0-1) and unfavourable (score 2-6) outcome.
- FINDINGS:165 (40.3%) alteplase-group patients and 143 (36.6%) placebo-group patients had favourable mRS outcomes (absolute difference 3.7%, p=0.277). In a posthoc analysis of mRS scores dichotomised for death or dependency, 222 (54.3%) alteplase-group and 180 (46.0%) placebo-group patients had favourable outcomes (score 0-2; absolute difference 8.3%, p=0.024). Treatment differences were similar whether patients were treated within 3 h or 3-6 h. 85 (10.6%) patients died, with no difference between treatment groups at day 90+/-14 days (43 alteplase, 42 placebo). Symptomatic intracranial haemorrhage occurred in 36 (8.8%) alteplase-group patients and 13 (3.4%) placebo-group patients.
- INTERPRETATION:The results do not confirm a statistical benefit for alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials. Despite the increased risk of intracranial haemorrhage, thrombolysis with alteplase at a dose of 0.9 mg/kg in selected patients may lead to a clinically relevant improvement in outcome.
- Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaemicstroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Bluhmki E, Chamorro A, Dávalos A, Machnig T, Sauce C, Wahlgren N, Wardlaw J, Hacke W.Lancet Neurol. 2009 Dec;8(12):1095-102. Epub 2009 Oct 21.Department of Statistics, Boehringer Ingelheim, Biberach, Germany.In the European Cooperative Acute Stroke Study III (ECASS III), alteplase administered 3.0-4.5 h after the onset of stroke symptoms resulted in a significant benefit in the primary endpoint (modified Rankin scale [mRS] score 0-1) versus placebo, with no difference in mortality between the treatment groups. Compared with the 0-3 h window, there was no excess risk of symptomatic intracranial haemorrhage. We assessed the usefulness of additional endpoints and did subgroup and sensitivity analyses to further investigate the benefit of alteplase.
- METHODS:In a double-blind, multicentre study in Europe, patients with acute ischaemic stroke were randomly assigned to intravenous alteplase (0.9 mg/kg bodyweight) or placebo. Additional outcome analyses included functional endpoints at day 90 or day 30 (mRS 0-1 [day 30], mRS 0-2, Barthel index > or =85, and global outcome statistic [day 30]) and treatment response (8-point improvement from baseline or 0-1 score on the National Institutes of Health stroke scale [NIHSS], and a stratified responder analysis by baseline NIHSS score). The subgroup analyses were based on the mRS 0-1 at day 90, symptomatic intracranial haemorrhage, and death. Analyses were by intention to treat and per protocol. This study is registered with ClinicalTrials.gov, number NCT00153036.
- FINDINGS:418 patients were assigned to alteplase and 403 to placebo. Although not significant in every case, all additional endpoints showed at least a clear trend in favour of alteplase. Alteplase was effective in various subgroups, including older patients (<65 years: odds ratio 1.61, 95% CI 1.05-2.48; > or =65 years: 1.15, 0.80-1.64; p=0.230), and the effectiveness was independent of the severity of stroke at baseline (NIHSS 0-9: 1.28, 0.84-1.96; NIHSS 10-19: 1.16, 0.73-1.84; NIHSS > or =20: 2.32, 0.61-8.90; p=0.631). The incidence of symptomatic intracranial haemorrhage seemed to be independent of previous antiplatelet drug use (no: 2.41, 1.09-5.33; yes: 2.33, 0.79-6.90; p=0.962) and time from onset of symptoms to treatment (181-210 min: 1.62, 0.26-10.25; 211-240 min: 1.97, 0.82-4.76; 241-270 min: 3.15, 1.01-9.79; p=0.761), but not of age dichotomised at 65 years (<65 years: 0.74, 0.28-1.96; > or =65 years: 5.79, 2.18-15.39; p=0.004).
- INTERPRETATION:Our results support the use of alteplase up to 4.5 h after the onset of stroke symptoms across a broad range of subgroups of patients who meet the requirements of the European product label but miss the approved treatment window of 0-3 h.
VLCBV and Hemorrhagic Transformation
Regional very low cerebral blood volume predicts hemorrhagic transformation better than diffusion-weighted imaging volume and thresholded apparent diffusion coefficient in acute ischemic stroke.
Campbell BC, Christensen S, Butcher KS, Gordon I, Parsons MW, Desmond PM, Barber PA, Levi CR, Bladin CF, De Silva DA, Donnan GA, Davis SM; EPITHET Investigators.Department of Neurology, Royal Melbourne Hospital, Grattan Street, Parkville VIC 3050,
- Australia.Preliminary studies have suggested that very low cerebral blood volume (VLCBV) predicts HT. We compared HT prediction by VLCBV and DWI using data from the EPITHET study.
METHODS:Normal-percentile CBV values were calculated from the nonstroke hemisphere. Whole-brain masks with CBV thresholds of the <0, 2.5, 5, and 10th percentiles were created. The volume of tissue with VLCBV was calculated within the acute DWI ischemic lesion. HT was graded as per ECASS criteria.
RESULTS:HT occurred in 44 of 91 patients. Parenchymal hematoma (PH) occurred in 13 (4 symptomatic) and asymptomatic hemorrhagic infarction (HI) in 31. The median volume of VLCBV was significantly higher in cases with PH. VLCBV predicted HT better than DWI lesion volume and thresholded apparent diffusion coefficient lesion volume in receiver operating characteristic analysis and logistic regression.A cutpoint at 2 mL VLCBV with the <2.5th percentile had 100% sensitivity for PH and, in patients treated with tissue plasminogen activator, defined a population with a 43% risk of PH (95% CI, 23% to 66%, likelihood ratio=16). VLCBV remained an independent predictor of PH in multivariate analysis with traditional clinical risk factors for HT.
CONCLUSIONS:VLCBV predicted HT after thrombolysis better than did DWI. Prediction was better in patients who recanalized. If validated in an independent cohort, the addition of VLCBV to prethrombolysis decision making may reduce the incidence of HT.
Markedly reduced apparent blood volume on bolus contrast magnetic resonance imaging as a predictor of hemorrhage after thrombolytic therapy for acute ischemic stroke.
Alsop DC, Makovetskaya E, Kumar S, Selim M, Schlaug G.Stroke. 2005 Apr;36(4):746-50. Epub 2005 Mar 3.Department of Radiology, Beth Israel Deaconess Medical CenterThis study sought to define characteristics of hemodynamic magnetic resonance imaging (MRI), which best predict hemorrhage.
- METHODS:Bolus contrast and diffusion MRI were performed before IV-tPA in 20 patients within the first 6 hours after symptom onset. Hemorrhage was assessed on follow-up MRI (n=15) and computed tomography (n=5) scans.
RESULTS:Of the 20 patients studied, 5 had detectable hemorrhage on follow-up scans. Blood volume maps demonstrated virtually no signal within much of the hemorrhagic region, indicating contrast did not arrive by the end of the imaging series (80 seconds). Within the hemodynamically abnormal region, a threshold of at least 126 voxels with blood volume <5% separated hemorrhagic with a sensitivity of 100% and a specificity of 73% (P<0.01). All subjects with hemorrhage were at least partially reperfused after thrombolysis, whereas most false-positives did not reperfuse (P<0.05). The number of low blood volume voxels within individual patients correlated with the number of voxels with apparent diffusion coefficient values <550x10(-6) mm2/s (P<0.019), another previously proposed predictor of hemorrhage.
CONCLUSIONS:Extremely low or completely absent contrast arrival may indicate tissue-at-risk for hemorrhage.
FLAIR and Hemorrhagic Transformation
- Fluid-attenuated inversion recovery hyperintensity in acute ischemic stroke may not predict hemorrhagic transformation.Campbell BC, Costello C, Christensen S, Ebinger M, Parsons MW, Desmond PM, Barber PA, Butcher KS, Levi CR, De Silva DA,Lansberg MG, Mlynash M, Olivot JM, Straka M, Bammer R, Albers GW, Donnan GA, Davis SM; EPITHET-DEFUSE Investigators.Cerebrovasc Dis. 2011;32(4):401-5. Epub 2011 Oct 8.Department of Medicine and Neurology, The Royal Melbourne Hospital, University of Melbourne, Parkville, Vic., Australia. Bruce.Campbell@mh.org.au
- We examined the prevalence of FLAIR hyperintensity in patients 3-6 h from stroke onset and its relationship to parenchymal hematoma (PH).
- METHODS:Baseline DWI and FLAIR imaging with subsequent hemorrhage detection (ECASS criteria) were prospectively obtained in patients 3-6 h after stroke onset from the pooled EPITHET and DEFUSE trials. FLAIR hyperintensity within the region of the acute DWI lesion was rated qualitatively (dichotomized as visually obvious or subtle (i.e. only visible after careful windowing)) and quantitatively (using relative signal intensity (RSI)). The association of FLAIR hyperintensity with hemorrhage was then tested alongside established predictors (very low cerebral blood volume (VLCBV) and diffusion (DWI) lesion volume) in logistic regression analysis.
- RESULTS:There were 49 patients with pre-treatment FLAIR imaging (38 received tissue plasminogen activator (tPA), 5 developed PH). FLAIR hyperintensity within the region of acute DWI lesion occurred in 48/49 (98%) patients, was obvious in 18/49 (37%) and subtle in 30/49 (61%). Inter-rater agreement was 92% (κ = 0.82). The prevalence of obvious FLAIR hyperintensity did not differ between studies obtained in the 3-4.5 h and 4.5-6 h time periods (40% vs. 33%, p = 0.77). PH was poorly predicted by obvious FLAIR hyperintensity (sensitivity 40%, specificity 64%, positive predictive value 11%). In univariate logistic regression, VLCBV (p = 0.02) and DWI lesion volume (p = 0.03) predicted PH but FLAIR lesion volume (p = 0.87) and RSI (p = 0.11) did not. In ordinal logistic regression for hemorrhage grade adjusted for age and baseline stroke severity (NIHSS), increased VLCBV (p = 0.002) and DWI lesion volume (p = 0.003) were associated with hemorrhage but FLAIR lesion volume (p = 0.66) and RSI (p = 0.35) were not.
- CONCLUSIONS:Visible FLAIR hyperintensity is almost universal 3-6 h after stroke onset and did not predict subsequent hemorrhage in this dataset. Our findings question the value of excluding patients with FLAIR hyperintensity from reperfusion therapies. Larger studies are required to clarify what implications FLAIR-positive lesions have for patient selection.