Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial
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.
Patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral haemorrhage (ICH) enrolled in the SPOTLIGHT trial (n= 50).
Recombinant activated factor VIIa (n= 19).
Placebo (n= 25).
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]).
Exploring Hematoma Expansion Shift with Recombinant Factor VIIa: A Pooled Analysis of Four Randomized Controlled Trials
Background: Hematoma expansion shift (HES) analysis can be used to assess the biological effect of a hemostatic therapy for intracerebral hemorrhage. In this study we applied HES analysis to individual patient data from four randomized controlled trials evaluating recombinant Factor VIIa (rFVIIa) 80 μg/kg to placebo. Methods: We generated polychotomous strata of HES using absolute growth thresholds (≤0mL/<6mL/≥6mL) and quintiles of percent volume change. The relationship between treatment and HES was assessed using proportional odds models. Differences in subgroups based on baseline volume (≥ or <20 mL) and time from symptom onset to treatment (≤ or >2 hours) were explored with testing for interactions. Results: The primary analysis included 721 patients. At 24 hours, 36% (134/369) of rFVIIa treated patients exhibited no hematoma expansion as compared to 25% of placebo (88/352) treated patients. Significant expansion (≥6 mL) was reduced by 10% in those treated with rFVIIa (acOR:0.57, 95% CI:0.43-0.75). An examination of percent change similarly showed a shift across the spectrum of expansion (acOR: 0.61, 95% CI: 0.47-0.80). In both groups, mild to moderate expansion was observed in 38 to 47% of patients, depending on the threshold used. Differences in absolute HES between the rFVIIa and placebo groups were more pronounced in patients with baseline hemorrhage volumes ≥20 mL (acOR 0.48, 95% CI: 0.30-0.76 versus <20 mL: acOR:0.67, 95% CI:0.47-0.95, p(interaction)= 0.02). No treatment interaction in patients treated within 2 or after 2 hours from onset was observed (acOR:0.42, 95% CI:0.19-0.91 versus >2 hours: acOR:0.59, 95% CI:0.44-0.79, p(interaction)=0.30). Conclusions: The association between rFVIIa and hematoma growth arrest is most pronounced in patients with larger baseline volumes but is evident across the full spectrum of treated patients.
Early Deterioration, Hematoma Expansion, and Outcomes in Deep Versus Lobar Intracerebral Hemorrhage: The FAST Trial
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.
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
Annals of Neurology. 2018
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.
Intraoperative intravenous administration of rFVIIa and hematoma volume after early surgery for spontaneous intracerebral hemorrhage: a randomized prospective phase II study
Minerva Anestesiologica. 2012;78((2):):168-75.
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.
The role of recombinant activated factor VII in neuro- surgical and neurocritical patients
Neurocirugia (Asturias, Spain). 2011;22((3):):209-23.
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.
Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial
Stroke; a Journal of Cerebral Circulation. 2010;41((1):):48-53.
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.
A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia
Journal of Clinical Neuroscience. 2010;17((6):):685-93.
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.
Haemostatic drug therapies for acute spontaneous intracerebral haemorrhage
Cochrane Database of Systematic Reviews. 2009;((4):):CD005951.
BACKGROUND Because spontaneous (non-traumatic) intracerebral haemorrhage (ICH) volume influences its outcome and a third of ICHs enlarge by a third within 24 hours of onset, early haemostatic drug therapy might improve outcome. This is an update of a Cochrane review first published in 2006. OBJECTIVES To examine the clinical effectiveness and safety of haemostatic drug therapies for acute ICH in a randomised controlled trial (RCT) design. SEARCH STRATEGY I searched the Cochrane Stroke Group Trials Register (last searched 26 June 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2009), MEDLINE (1966 to June 2009) and EMBASE (1980 to June 2009). In an effort to identify further published, ongoing and unpublished studies I scanned bibliographies of relevant articles, searched international registers of clinical trials and research, and contacted authors and pharmaceutical companies. SELECTION CRITERIA I sought RCTs of any haemostatic drug therapy for acute ICH, compared against placebo or open control, with relevant clinical outcome measures. DATA COLLECTION AND ANALYSIS Two authors independently applied the inclusion criteria, reviewed the relevant studies, and extracted data. MAIN RESULTS I found five phase II RCTs and one phase III RCT, involving 1398 adults aged 18 years or over, within four hours of ICH onset: 423 participants received placebo and 975 participants received haemostatic drugs (two received epsilon-aminocaproic acid (EACA) and 973 received recombinant activated factor VII (rFVIIa)). Haemostatic drugs did not significantly reduce 90-day case fatality after ICH (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.58 to 1.25), and rFVIIa did not significantly reduce death or dependence on the modified Rankin Scale (grades 4 to 6) within 90 days of ICH (RR 0.91, 95% CI 0.72 to 1.15). There was a trend towards more participants on rFVIIa experiencing thromboembolic serious adverse events (RR 1.37, 95% CI 0.74 to 2.55) AUTHORS' CONCLUSIONS Haemostatic drugs cannot be recommended for the treatment of acute spontaneous ICH in clinical practice, but a large RCT would be justified.
Risk of thromboembolic events in controlled trials of rFVIIa in spontaneous intracerebral hemorrhage
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.