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Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial
Al-Ajlan FS, Gladstone DJ, Song D, Thorpe KE, Swartz RH, Butcher KS, Del Campo M, Dowlatshahi D, Gensicke H, Lee GJ, et al
Stroke. 2023
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Editor's Choice
Abstract
BACKGROUND In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 μg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT01359202.
PICO Summary
Population
Patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral haemorrhage (ICH) enrolled in the SPOTLIGHT trial (n= 50).
Intervention
Recombinant activated factor VIIa (n= 19).
Comparison
Placebo (n= 25).
Outcome
This prespecified analysis aimed to investigate the impact of delays from baseline imaging to study drug administration on haematoma expansion. Haematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total haematoma volume (intracerebral haemorrhage + intraventricular haemorrhage) change between the 3 scans was calculated as an estimate of how much haematoma expansion occurred before and after studying drug administration. Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2 - 2.6). Median time from baseline CT to study drug was 62.5 (55 - 80) minutes, and from study drug to early post-dose CT was 19 (14.5 - 30) minutes. Median (interquartile range) total haematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8 - 8.3) in the placebo arm. Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm. Total haematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted haematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI: 0.71 - 1.43]). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI: 0.994 - 1.003]).
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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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Final Results of the RHAPSODY trial: A multi-center, Phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3K3A-APC, a Recombinant Variant of Human Activated Protein C, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke
Lyden P, Pryor KE, Coffey CS, Cudkowicz M, Conwit R, Jadhav A, Sawyer RN Jnr, Claassen J, Adeoye O, Song S, et al
Annals of Neurology. 2018
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Abstract
OBJECTIVE Agonism of the protease activated receptor (PAR) 1 by activated protein C (APC) provides neuroprotection and vasculoprotection in experimental neuro-injury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurologic injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded, trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. METHODS The NeuroNEXT trial RHAPSODY used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360 and 540mug/kg 3K3A-APC. After intravenous tissue plasminogen activator, intraarterial mechanical thrombectomy, or both, patients were randomized to one of the four doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. RESULTS Between January 2015 and July 2017 we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest dose 3K3A-APC tested, 540mug/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p=0.046), and total hemorrhage volume from an average of 2.1+/-5.8 mL in placebo to 0.8+/-2.1 mL in the combined treatment arms (p=0.066). INTERPRETATION RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540mug/kg for the PAR1 active cytoprotectant 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. This article is protected by copyright. All rights reserved.
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A double-blind, randomized, controlled study to explore the efficacy of rFVIIa on intraoperative blood loss and mortality in patients with severe acute pancreatitis
Lu J, Liao LM, Geng YX, Wang X, Tong ZH, Ke L, Li WQ, Li N, Li JS
Thrombosis Research. 2014;133((4):):574-8.
Abstract
BACKGROUND Severe acute pancreatitis is a life-threatening disease. Patients with peripancreatic necrotic infection often require surgical removal of necrotic infected tissue and a wide debridement will cause blood loss and worsen the condition. AIM: To assess whether treatment with NovoSeven, a recombinant activated FVII (rFVIIa), could improve coagulation function and therefore reduce blood loss, blood transfusion and all-cause mortality during necrosectomy in patients with infected necrosis secondary to severe acute pancreatitis. MATERIALS AND METHODS Severe acute pancreatitis patients admitted to Nanjing Jinling Hospital for necrosectomy were enrolled and randomized to receive either standard treatment or standard treatment plus an intravenous infusion of rFVIIa (40mug per kilogram of body weight per hour) before operation. The prospectively defined primary end points were perioperative coagulation parameters (prothrombin time, activated partial thromboplastin time), blood transfusion unit and blood loss. The secondary end points were operation time, ICU stay and all-cause mortality at 28days after the operation. RESULTS A total of 64 patients were enrolled (31 in the rFVIIa group and 33 in the control group). Treatment with rFVIIa was associated with a reduction in operation time, red blood cell and fresh froze plasma transfusion, blood loss and prothrombin time compared to the control group (p<0.05 for all). Activated partial thromboplastin time and mortality were similar between the two groups (P>0.05). CONCLUSION Treatment with rFVIIa significantly improved the extrinsic coagulation function in patients with severe acute pancreatitis and was associated with decreased risk of bleeding. However, rFVIIa did not improve intrinsic coagulation or reduce over-cause mortality. Clinical Trial Registration Number: ChiCTR-TRC-1300389. Copyright 2014 Elsevier Ltd. All rights reserved.
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Effect of recombinant Factor VIIa on outcome of acute variceal bleeding: an individual patient based meta-analysis of two controlled trials
Bendtsen F, D'Amico G, Rusch E, de Franchis R, Andersen PK, Lebrec D, Thabut D, Bosch J
Journal of Hepatology. 2014;61((2)):252-9.
Abstract
BACKGROUND & AIMS Two randomized controlled studies have evaluated the effect of recombinant Factor VIIa (rFVIIa) on variceal bleeding in cirrhosis without showing significant benefit. The aim of the present study was to perform a meta-analysis of the two trials on individual patient data with special focus on high risk patients. METHODS The primary outcome measure was the effect of rFVIIa on a composite five day endpoint: failure to control bleeding, 5-day rebleeding or death. Analysis was based on intention to treat. High risk was defined as active bleeding on endoscopy while under vasoactive drug infusion and Child-Pugh score >8. RESULTS 497 patients were eligible for the meta-analysis; 308 (62%) had active variceal bleeding at endoscopy (oozing or spurting) and 283 of these had a Child-Pugh score >8. Analysis on the composite endpoint in all patients with bleeding from oesophageal varices did not show any beneficial treatment effect. However, failure rate for the primary composite end-point was significantly lower in treated patients with active bleeding at endoscopy (17%) compared to placebo (26%, p=0.049). This difference was highly significant in patients with Child-Pugh score >8 and active bleeding at endoscopy (rFVIIa 16%, placebo 27%; p=0.023). No significant treatment effect was found at 42 days. Five thromboembolic events occurred in rFVIIa treated patients compared to none in placebo treated patients. CONCLUSIONS The current meta-analysis shows a beneficial effect of rFVIIa on the primary composite endpoint of control of acute bleeding, prevention of rebleeding day 1-5 and 5-day mortality in patients with advanced cirrhosis and active bleeding from oesophageal varices at endoscopy. A major drawback of the treatment is a potential increased risk of arterial thrombo-embolic events. This treatment might be considered in patients with lack of control of bleeding after standard treatment.Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. RN 0 (Recombinant Proteins). 0 (recombinant FVIIa). EC 3-4-21-21 (Factor VIIa).
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Intraoperative intravenous administration of rFVIIa and hematoma volume after early surgery for spontaneous intracerebral hemorrhage: a randomized prospective phase II study
Imberti R, Pietrobono L, Klersy C, Gamba G, Iotti G, Cornara G
Minerva Anestesiologica. 2012;78((2):):168-75.
Abstract
BACKGROUND Surgery of spontaneous supratentorial intracerebral hemorrhage (ICH), especially if performed early, can be complicated by rebleeding, a condition that can worsen the outcome. We evaluated the effect of recombinant activated factor VII (rFVIIa) on postoperative rebleeding. METHODS In this randomized, open-label, single-blinded study, 21 patients with spontaneous supratentorial ICH diagnosed by computed tomography (CT) scan were treated with intravenous rFVIIa (100 mcg/Kg b.w., N=13) or placebo (N=8). Hematoma volume was assessed using CT scan immediately, 18-30 hours, and 5-7 days after hematoma evacuation. The primary endpoint was a hematoma volume at 18-30 hours after surgery. All CT scans were evaluated at one center by the same investigator who was unaware of the treatment. Hematoma volume was measured using dedicated software. RESULTS At baseline, the hematoma volume was 59.2+/-27.4 and 71.5+/-32.1 mL in the rFVIIa and placebo group, respectively. Hematoma evacuation resulted in significantly smaller ICH volumes that were similar in the rFVIIa and placebo group at 18-30 hours after surgery (15.9+/-14.2 mL and 18+/-15.1 mL, respectively; mean difference 2.1 mL, 95% confidence interval -12.1 to 16.2, P=0.76 (0.03 mL after adjustment for baseline value)). The frequencies of deep venous thrombosis, myocardial infarction, troponin I elevation and cerebral ischemia were similar in both groups. CONCLUSION In this pilot study, intraoperative, intravenous rFVIIa administration did not modify hematoma volume after early ICH surgery. However, the 95% CI was wide, which indicates considerable uncertainty. Therefore, our results do not disprove the potential benefit of rFVIIa administration, which could be shown in a larger study.
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Human recombinant activated factor VII for upper gastrointestinal bleeding in patients with liver diseases
Marti-Carvajal AJ, Karakitsiou DE, Salanti G
Cochrane Database of Systematic Reviews. 2012;((3):):CD004887.
Abstract
BACKGROUND Mortality from upper gastrointestinal bleeding in patients with liver disease is high. Recombinant human activated factor VII (rHuFVIIa) has been suggested for patients with liver disease and upper gastrointestinal bleeding. OBJECTIVES To assess the beneficial and harmful effects of rHuFVIIa in patients with liver disease and upper gastrointestinal bleeding. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4, 2011), MEDLINE (1948 to December 2011), EMBASE (1980 to December 2011), Science Citation Index Expanded (1900 to December 2011), and LILACS (December 2011). We sought additional randomised trials from the reference lists of the trials and reviews identified through the electronic searches. SELECTION CRITERIA Randomised clinical trials. DATA COLLECTION AND ANALYSIS Outcome data from randomised clinical trials were extracted and were presented using random-effects model meta-analyses. Data on the risk of bias in the included trials were also extracted. MAIN RESULTS We included two trials with 493 randomised participants with various Child-Pugh scores. The trials had a low risk of bias. The rHuFVIIa administration did not reduce the risk of mortality within five days (21/288 (7. 3%) versus 15/205 (7. 3%); risk ratio (RR) 0. 88, 95% confidence interval (CI) 0. 48 to 1. 64, I(2) = 49%) and within 42 days (5/286 (1. 7%) versus 36/205 (17. 6%); RR 1. 01, 95% CI 0. 55 to 1. 87, I(2) = 55%) when compared with placebo. Trial sequential analysis demonstrated that there is sufficient evidence to exclude that rHuFVIIa decreases mortality by 80%, but there is insufficient evidence to exclude smaller effects. The rHuFVIIa did not increase the risk of adverse events by number of patients (218/297 (74%) and 164/210 (78%); RR 0. 94, 95% CI 0. 84 to 1. 04, I(2) = 1%), serious adverse events by adverse events reported (164/590 (28%) versus 123/443 (28%); RR 0. 91, 95% CI 0. 75 to 1. 11, I(2) = 0%), and thromboembolic adverse events (16/297 (5. 4%) versus 14/210 (6. 7%); RR 0. 80, 95% CI 0. 40 to 1. 60, I(2) = 0%) when compared with placebo. AUTHORS' CONCLUSIONS We found no evidence to support or reject the administration of rHuFVIIa for patients with liver disease and upper gastrointestinal bleeding. Further adequately powered randomised clinical trials are needed in order to evaluate the proper role of rHuFVIIa for treating upper gastrointestinal bleeding in patients with liver disease. Although the results are based on trials with low risk of bias, the heterogeneity and the small sample size result in rather large confidence intervals that cannot exclude the possibility that the intervention has some beneficial or harmful effect. Further trials with alow risk of bias are required to make more confident conclusions about the effects of the intervention.
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The role of recombinant activated factor VII in neuro- surgical and neurocritical patients
Rama-Maceiras P, Ingelmo-Ingelmo I, Fabregas-Julia N, Hernandez-Palazon J
Neurocirugia (Asturias, Spain). 2011;22((3):):209-23.
Abstract
Central nervous system haemorrhage is a severe pathology, as a small amount of bleeding inside the brain can result in devastating consequences. Haemostatic agents might decrease the consequences of intra-cranial bleeding, whichever spontaneous, traumatic, or anticoagulation treatment etiology. Proacogulant recombinant activated factor VII (rFVIIa) has been given after central nervous system bleeding, with an off-label indication. In this update, we go over the drug mechanism of action, its role in the treatment of central nervous system haemorrhage and the published evidences regarding this subject. We carried out a literature review concerning the treatment with rFVIIa in central nervous system haemorrhage, neurocritical pathologies and neurosurgical procedures, searching in MEDLINE and in clinical trials registry: http://clinicaltrials. gov (last review September 2010), as well as performing a manual analysis of collected articles, looking for aditional references. The results of randomized clinical trials do not support the systematic administration of rFVIIa for spontaneous intracranial cerebral haemorrhage. In other central nervous system related haemorrhages, the current available data consist on retrospective studies, expert opinion or isolated case reports.
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A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia
Yuan ZH, Jiang JK, Huang WD, Pan J, Zhu JY, Wang JZ
Journal of Clinical Neuroscience. 2010;17((6):):685-93.
Abstract
Hematoma growth is common in intracerebral hemorrhage (ICH) and is associated with a poor outcome for patients. To evaluate the efficacy and safety of recombinant activated factor VII (rFVIIa) used as a hemostatic agent in patients with ICH without hemophilia, we searched Medline, Scopus, the Cochrane Library, Clinicaltrials.gov and the Stroke Trials Directory. Five randomized controlled trials were selected for analysis. Although rFVIIa can reduce the change in ICH volume, there was no significant difference in mortality, modified Rankin Scale (mRS) score or extended Glasgow Outcome Scale (GOS-E) score in patients treated with rFVIIa or placebo. There was a significant increase in arterial thromboembolic adverse events (TAE) in patients treated with rFVIIa. There was an increase in deep vein thrombosis in patients with spontaneous ICH and traumatic ICH. In conclusion, the use of rFVIIa reduces the growth of the hematoma but does not improve patient survival or functional outcome after ICH; in addition, rFVIIa increases the incidence of arterial TAE.
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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.
