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Early Deterioration, Hematoma Expansion, and Outcomes in Deep Versus Lobar Intracerebral Hemorrhage: The FAST Trial
Kuohn LR, Witsch J, Steiner T, Sheth KN, Kamel H, Navi BB, Merkler AE, Murthy SB, Mayer SA
Stroke. 2022;:101161strokeaha121037974
Abstract
BACKGROUND In patients with intracerebral hemorrhage (ICH), it is unclear whether early neurological deterioration, hematoma expansion (HE), and outcome vary by supratentorial ICH location (deep versus lobar). Herein, we assessed these relationships in a clinical trial cohort that underwent brain imaging early after symptom onset. We hypothesized that HE would occur more frequently, and outcome would be worse in patients with deep ICH. METHODS We performed a post hoc analysis of the FAST (Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment) trial including all patients with supratentorial hemorrhage. Enrolled patients underwent brain imaging within 3 hours of symptom onset and 24 hours after randomization. Multivariable regression was used to test the association between ICH location and 3 outcomes: HE (increase of ≥33% or 6mL), early neurological deterioration (decrease in Glasgow Coma Scale score ≥2 points or increase in National Institutes of Health Stroke Scale ≥4 points within 24 hours of admission), and 90-day outcome (modified Rankin Scale). RESULTS Of 841 FAST trial patients, we included 728 (mean age 64 years, 38% women) with supratentorial hemorrhages (deep n=623, lobar n=105). HE (44 versus 27%, P=0.001) and early neurological deterioration (31 versus 17%, P=0.001) were more common in lobar hemorrhages. Deep hemorrhages were smaller than lobar hemorrhages at baseline (12 versus 35mL, P<0.001) and 24 hours (14 versus 38mL, P<0.001). Unadjusted 90-day outcome was worse in lobar compared with deep ICH (median modified Rankin Scale score 5 versus 4, P=0.03). However, when adjusting for variables included in the ICH score including ICH volume, deep location was associated with worse and lobar location with better outcome (odds ratio lobar location, 0.58 [95% CI, 0.38-0.89]; P=0.01). CONCLUSIONS In this secondary analysis of randomized trial patients, lobar ICH location was associated with larger ICH volume, more HE and early neurological deterioration, and worse outcome than deep ICH. After adjustment for prognostic variables, however, deep ICH was associated with worse outcome, likely due to their proximity to eloquent brain structures.
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Tranexamic Acid for Prevention of Hematoma Expansion in Intracerebral Hemorrhage Patients With or Without Spot Sign
Ovesen C, Jakobsen JC, Gluud C, Steiner T, Law Z, Flaherty K, Dineen RA, Christensen LM, Overgaard K, Rasmussen RS, et al
Stroke. 2021;:Strokeaha120032426
Abstract
BACKGROUND AND PURPOSE The computed tomography angiography or contrast-enhanced computed tomography based spot sign has been proposed as a biomarker for identifying on-going hematoma expansion in patients with acute intracerebral hemorrhage. We investigated, if spot-sign positive participants benefit more from tranexamic acid versus placebo as compared to spot-sign negative participants. METHODS TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) was a randomized, placebo-controlled clinical trial recruiting acutely hospitalized participants with intracerebral hemorrhage within 8 hours after symptom onset. Local investigators randomized participants to 2 grams of intravenous tranexamic acid or matching placebo (1:1). All participants underwent computed tomography scan on admission and on day 2 (24±12 hours) after randomization. In this sub group analysis, we included all participants from the main trial population with imaging allowing adjudication of spot sign status. RESULTS Of the 2325 TICH-2 participants, 254 (10.9%) had imaging allowing for spot-sign adjudication. Of these participants, 64 (25.2%) were spot-sign positive. Median (interquartile range) time from symptom onset to administration of the intervention was 225.0 (169.0 to 310.0) minutes. The adjusted percent difference in absolute day-2 hematoma volume between participants allocated to tranexamic versus placebo was 3.7% (95% CI, -12.8% to 23.4%) for spot-sign positive and 1.7% (95% CI, -8.4% to 12.8%) for spot-sign negative participants (P(heterogenity)=0.85). No difference was observed in significant hematoma progression (dichotomous composite outcome) between participants allocated to tranexamic versus placebo among spot-sign positive (odds ratio, 0.85 [95% CI, 0.29 to 2.46]) and negative (odds ratio, 0.77 [95% CI, 0.41 to 1.45]) participants (P(heterogenity)=0.88). CONCLUSIONS Data from the TICH-2 trial do not support that admission spot sign status modifies the treatment effect of tranexamic acid versus placebo in patients with acute intracerebral hemorrhage. The results might have been affected by low statistical power as well as treatment delay. REGISTRATION URL: http://www.controlled-trials.com; Unique identifier: ISRCTN93732214.
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Regional differences in the response to acute blood pressure lowering after cerebral hemorrhage
Toyoda K, Palesch YY, Koga M, Foster L, Yamamoto H, Yoshimura S, Ihara M, Fukuda-Doi M, Okazaki S, Tanaka K, et al
Neurology. 2020
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Abstract
OBJECTIVE To compare the impact of intensive blood pressure (BP) lowering right after intracerebral hemorrhage (ICH) on clinical and hematoma outcomes among patients from different geographic locations, we performed a prespecified sub-analysis of the randomized, multi-national, two-group, open-label trial to determine the efficacy of rapidly lowering BP in hyperacute ICH (ATACH-2), involving 537 patients from East Asia and 463 recruited outside of Asia. METHODS Eligible patients were randomly assigned to a systolic BP (SBP) target of 110-139 mmHg (intensive treatment) or 140-179 mmHg (standard treatment). Pre-defined outcomes were: poor functional outcome (modified Rankin Scale score of 4-6 at 90 days), death within 90 days, hematoma expansion at 24 hours; and cardio-renal adverse events within 7 days. RESULTS Poor functional outcomes (32.0% versus 45.9%), death (1.9% versus 13.3%), and cardio-renal adverse events (3.9% versus 11.2%) occurred significantly less in patients from Asia than those outside of Asia. The treatment-by-cohort interaction was not significant for any outcomes. Only patients from Asia showed a lower incidence of hematoma expansion with intensive treatment (adjusted RR 0.56, 95% CI 0.38-0.83). Both Asian (3.53, 1.28-9.64) and non-Asian cohorts (1.71, 1.00-2.93) showed a higher incidence of cardio-renal adverse events with intensive treatment. CONCLUSIONS Poor functional outcomes and death 90 days after ICH were less common in patients from East Asia than those outside of Asia. Hematoma expansion, a potential predictor for poor clinical outcome, was attenuated by intensive BP lowering only in the Asian cohort. CLINICALTRIALSGOV IDENTIFIER NCT01176565. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that, for patients from East Asia with intracerebral hemorrhage, intensive blood pressure lowering significantly reduces the risk of hematoma expansion.
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Outcomes of Intensive Systolic Blood Pressure Reduction in Patients With Intracerebral Hemorrhage and Excessively High Initial Systolic Blood Pressure: Post Hoc Analysis of a Randomized Clinical Trial
Qureshi AI, Huang W, Lobanova I, Barsan WG, Hanley DF, Hsu CY, Lin CL, Silbergleit R, Steiner T, Suarez JI, et al
JAMA neurology. 2020
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Abstract
IMPORTANCE The safety and efficacy of intensive systolic blood pressure reduction in patients with intracerebral hemorrhage who present with systolic blood pressure greater than 220 mm Hg appears to be unknown. OBJECTIVE To evaluate the differential outcomes of intensive (goal, 110-139 mm Hg) vs standard (goal, 140-179 mm Hg) systolic blood pressure reduction in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more vs less than 220 mm Hg. DESIGN, SETTING, AND PARTICIPANTS This post hoc analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage-II trial was performed in November 2019 on data from the multicenter randomized clinical trial, which was conducted between May 2011 to September 2015. Patients with intracerebral hemorrhage and initial systolic blood pressure of 180 mm Hg or more, randomized within 4.5 hours after symptom onset, were included. INTERVENTIONS Intravenous nicardipine infusion titrated to goals. MAIN OUTCOMES AND MEASURES Neurological deterioration and hematoma expansion within 24 hours and death or severe disability at 90 days, plus kidney adverse events and serious adverse events until day 7 or hospital discharge. RESULTS A total of 8532 patients were screened, and 999 individuals (mean [SD] age, 62.0 [13.1] years; 620 men [62.0%]) underwent randomization and had an initial SBP value. Among 228 participants with initial systolic blood pressures of 220 mm Hg or more, the rate of neurological deterioration within 24 hours was higher in those who underwent intensive (vs standard) systolic blood pressure reduction (15.5% vs 6.8%; relative risk, 2.28 [95% CI, 1.03-5.07]; P = .04). The rate of death and severe disability (39.0% vs 38.4%; relative risk, 1.02 [95% CI, 0.73-1.78]; P = .92) was not significantly different between the 2 groups. There was a significantly higher rate of kidney adverse events in participants randomized to intensive systolic blood pressure reduction (13.6% vs 4.2%; relative risk, 3.22 [95% CI, 1.21-8.56]; P = .01), but no difference was observed in the rate of kidney serious adverse events. CONCLUSIONS AND RELEVANCE The higher rate of neurological deterioration within 24 hours associated with intensive treatment in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more, without any benefit in reducing hematoma expansion at 24 hours or death or severe disability at 90 days, warrants caution against generalization of recommendations for intensive systolic blood pressure reduction.
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Haemostatic therapies for acute spontaneous intracerebral haemorrhage
Al-Shahi Salman R, Law Z K, Bath P M, Steiner T, Sprigg N
The Cochrane Database of Systematic Reviews. 2018;(4):CD005951.
Abstract
BACKGROUND Outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume; up to one-third of ICHs enlarge within 24 hours of onset. Early haemostatic therapy might improve outcome by limiting haematoma growth. This is an update of a Cochrane Review first published in 2006, and last updated in 2009. OBJECTIVES To examine 1) the effectiveness and safety of individual classes of haemostatic therapies, compared against placebo or open control, in adults with acute spontaneous intracerebral haemorrhage, and 2) the effects of each class of haemostatic therapy according to the type of antithrombotic drug taken immediately before ICH onset (i.e. anticoagulant, antiplatelet, or none). SEARCH METHODS We searched the Cochrane Stroke Trials Register, CENTRAL; 2017, Issue 11, MEDLINE Ovid, and Embase Ovid on 27 November 2017. In an effort to identify further published, ongoing, and unpublished randomised controlled trials (RCT), we scanned bibliographies of relevant articles and searched international registers of RCTs in November 2017. SELECTION CRITERIA We sought randomised controlled trials (RCTs) of any haemostatic intervention (i.e. pro-coagulant treatments such as coagulation factors, antifibrinolytic drugs, or platelet transfusion) for acute spontaneous ICH, compared with placebo, open control, or an active comparator, reporting relevant clinical outcome measures. DATA COLLECTION AND ANALYSIS Two authors independently extracted data, assessed risk of bias, and contacted corresponding authors of eligible RCTs for specific data if they were not provided in the published report of an RCT. MAIN RESULTS We included 12 RCTs involving 1732 participants. There were seven RCTs of blood clotting factors versus placebo or open control involving 1480 participants, three RCTs of antifibrinolytic drugs versus placebo or open control involving 57 participants, one RCT of platelet transfusion versus open control involving 190 participants, and one RCT of blood clotting factors versus fresh frozen plasma involving five participants. We were unable to include two eligible RCTs because they presented aggregate data for adults with ICH and other types of intracranial haemorrhage. We identified 10 ongoing RCTs. Across all seven criteria in the 12 included RCTs, the risk of bias was unclear in 37 (44%), high in 16 (19%), and low in 31 (37%). Only one RCT was at low risk of bias in all criteria.In one RCT of platelet transfusion versus open control for acute spontaneous ICH associated with antiplatelet drug use, there was a significant increase in death or dependence (modified Rankin Scale score 4 to 6) at day 90 (70/97 versus 52/93; risk ratio (RR) 1.29, 95% confidence interval (CI) 1.04 to 1.61, one trial, 190 participants, moderate-quality evidence). All findings were non-significant for blood clotting factors versus placebo or open control for acute spontaneous ICH with or without surgery (moderate-quality evidence), for antifibrinolytic drugs versus placebo (moderate-quality evidence) or open control for acute spontaneous ICH (moderate-quality evidence), and for clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use (no evidence). AUTHORS' CONCLUSIONS Based on moderate-quality evidence from one trial, platelet transfusion seems hazardous in comparison to standard care for adults with antiplatelet-associated ICH.We were unable to draw firm conclusions about the efficacy and safety of blood clotting factors for acute spontaneous ICH with or without surgery, antifibrinolytic drugs for acute spontaneous ICH, and clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use.Further RCTs are warranted, and we await the results of the 10 ongoing RCTs with interest.
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Hemostatic Therapies For Acute Spontaneous Intracerebral Hemorrhage
Law ZK, Salman RA, Bath PM, Steiner T, Sprigg N
Stroke. 2018;49((8)):e271-e272.
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Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial
Diringer MN, Skolnick BE, Mayer SA, Steiner T, Davis SM, Brun NC, Broderick JP
Stroke; a Journal of Cerebral Circulation. 2010;41((1):):48-53.
Abstract
BACKGROUND AND PURPOSE Patients with intracerebral hemorrhage have a high risk of thromboembolic events (TEs) due to advanced age, hypertension, atherosclerosis, diabetes, and immobility. Use of recombinant activated factor VII (rFVIIa) could increase TEs in high-risk patients. Factor Seven for Acute Hemorrhagic Stroke (FAST) trial data were reviewed to define the frequency of and risk factors for TE with rFVIIa. METHODS Eight hundred forty-one patients presenting <3 hours after spontaneous intracerebral hemorrhage were randomized to 20 or 80 microg/kg of rFVIIa or placebo. Those with Glasgow Coma Scale score <5, planned early surgery, coagulopathy, or recent TE were excluded. Myocardial, cerebral, or venous TEs were subject to detailed reporting and expedited local review. Additionally, a blinded Data Monitoring Committee reviewed all electrocardiograms, centrally analyzed troponin I values, and CT scans. RESULTS There were 178 arterial and 47 venous TEs. Venous events were similar across groups. There were 49 (27%) arterial events in the placebo group, 47 (26%) in the 20-microg/kg group, and 82 (46%) in the 80 microg/kg group (P=0. 04). Of the myocardial events, 38 were investigator-reported and 103 identified by the Data Monitoring Committee. They occurred in 17 (6. 3%) placebo and 57 (9. 9%) rFVIIa patients (P=0. 09). Arterial TEs were associated with: receiving 80 microg/kg rFVIIa (OR=2. 14; P=0. 031), signs of cardiac or cerebral ischemia at presentation (OR=4. 19; P=0. 010), age (OR=1. 14/5 years; P=0. 0123), and prior use of antiplatelet agents (OR=1. 83; P=0. 035). Ischemic strokes possibly related to study drug occurred in 7, 5, and 8 patients in the placebo, 20 microg/kg, and 80-microg/kg groups, respectively. CONCLUSIONS Higher doses of rFVIIa in a high-risk population are associated with a small increased risk of what are usually minor cardiac events. Demonstration of the ability of rFVIIa to improve outcome in future studies should be driven by its effectiveness in slowing bleeding outweighting the risk of a small increase in arterial TEs.
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Risk of thromboembolic events in controlled trials of rFVIIa in spontaneous intracerebral hemorrhage
Diringer MN, Skolnick BE, Mayer SA, Steiner T, Davis SM, Brun NC, Broderick JP
Stroke. 2008;39((3):):850-6.
Abstract
BACKGROUND AND PURPOSE Recombinant activated factor VII (rFVIIa) reduces hematoma expansion and improves outcome after intracerebral hemorrhage (ICH), with an apparent increase in nonfatal thromboembolic events (TEs) with higher doses. Despite low incidences of such events in rFVIIa-treated hemophiliacs, the frequency in older patients with more atherosclerosis and immobility has yet to be defined. METHODS Data were pooled from 3 randomized placebo-controlled studies in patients diagnosed within 3 hours of spontaneous ICH who received a single dose of rFVIIa (5 to 160 microg/kg; n=371) or placebo (n=115). Clinical/laboratory evaluations, lower extremity Doppler studies, and 72-hour CT scans were used to monitor for TEs. Adverse events occurring while hospitalized and serious events occurring through day 90 were carefully reviewed. RESULTS There was no overall increase in risk of total TEs in rFVIIa-treated patents; however, there were more arterial, but not venous, TEs in the high dose group (120 to 160 microg/kg) compared with placebo (5. 4% versus 1. 7%; P=0. 13). Arterial events occurring within 7 days of drug administration classified as possibly or probably associated with study drug included myocardial ischemia (n=9, 8 were non-ST-segment elevation and non-Q-wave events; 2 of the 9 had sequelae) and ischemic stroke (n=9, 4 of which had likely causes other than rFVIIa). Regression analysis identified high doses (120 to 160 microg/kg) of rFVIIa as the only factor associated with arterial TEs (odds ratio=6. 75; P=0. 02). CONCLUSIONS There appears to be a increased risk of arterial TEs associated with higher doses of rFVIIa in ICH patients as compared with placebo. Further studies are underway to identify specific factors associated with these events and to define the dose that maximizes benefit and minimizes risk.
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Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage
Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T, FAST Trial Investigators
The New England Journal of Medicine. 2008;358((20):):2127-37.
Abstract
BACKGROUND Intracerebral hemorrhage is the least treatable form of stroke. We performed this phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes. METHODS We randomly assigned 841 patients with intracerebral hemorrhage to receive placebo (268 patients), 20 microg of rFVIIa per kilogram of body weight (276 patients), or 80 microg of rFVIIa per kilogram (297 patients) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke. RESULTS Treatment with 80 microg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the intracerebral hemorrhage at 24 hours was 26% in the placebo group, as compared with 18% in the group receiving 20 microg of rFVIIa per kilogram (P=0. 09) and 11% in the group receiving 80 microg (P<0. 001). The growth in volume of intracerebral hemorrhage was reduced by 2. 6 ml (95% confidence interval [CI], -0. 3 to 5. 5; P=0. 08) in the group receiving 20 microg of rFVIIa per kilogram and by 3. 8 ml (95% CI, 0. 9 to 6. 7; P=0. 009) in the group receiving 80 microg, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 microg of rFVIIa per kilogram, and 29% in the group receiving 80 microg). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 microg of rFVIIa than in the placebo group (9% vs. 4%, P=0. 04). CONCLUSIONS Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. (ClinicalTrials. gov number, NCT00127283 [ClinicalTrials. gov]. ).
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Impact of recombinant activated factor VII on health-related quality of life after intracerebral hemorrhage
Diringer MN, Ferran JM, Broderick J, Davis S, Mayer SA, Steiner T, Brun NC, Skolnick BE, Christensen MC
Cerebrovascular Diseases (Basel, Switzerland). 2007;24((2-3):):219-25.
Abstract
BACKGROUND We recently demonstrated that recombinant activated factor VII (rFVIIa) given to patients presenting within 3 h of acute spontaneous intracerebral hemorrhage (ICH) reduces mortality (18% vs. 29%) and poor outcome (modified Rankin Scale, mRS, 4-6, 53 vs. 69%). This analysis was performed to determine the impact of rFVIIa on health-related quality of life (HRQoL) in those patients. METHODS In a prospective, randomized controlled trial, 399 patients (mean age, 66 years) received placebo, 40, 80 or 160 microg/kg of rFVIIa within 4 h of acute ICH. At 90 days, HRQoL was assessed with the EuroQoL (EQ-5D), a 5-dimensional measure of health which also includes the Visual Analogue Scale. Additionally, each level of the 90-day mRS was adjusted, using 4 different previously published utility values, to obtain a clearer picture of perceived HRQoL. RESULTS Among the 5 dimensions of EQ-5D, only mobility rating was significantly better for rFVIIa-treated patients (serious problems, 34 vs. 54%; p = 0. 01). Yet, the utility value (scaled 1. 0 = perfect health and 0. 0 = dead) associated with the composite EQ-5D demonstrated significantly better HRQoL (0. 48 vs. 0. 36; p = 0. 01). This was also true for the EQ-5D Visual Analogue Scale score (44 vs. 36; p = 0. 04). Finally, all 4 algorithms for applying utility scores to the mRS indicated that rFVIIa was associated with significantly better perceived HRQoL (all p < 0. 006). CONCLUSIONS Treatment with rFVIIa within 4 h of acute spontaneous ICH improves HRQoL.