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1.
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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2.
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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3.
Recombinant factor VIIA in traumatic intracerebral hemorrhage: results of a dose-escalation clinical trial
Narayan RK, Maas AI, Marshall LF, Servadei F, Skolnick BE, Tillinger MN, rFVIIa Traumatic ICHStudy Group
Neurosurgery. 2008;62((4):):776-86; discussion 786-8.
Abstract
OBJECTIVE Intracerebral hemorrhages, whether spontaneous or traumatic (tICH), often expand, and an association has been described between hemorrhage expansion and worse clinical outcomes. Recombinant factor VIIa (rFVIIa) is a hemostatic agent that has been shown to limit hemorrhage expansion and which, therefore, could potentially reduce morbidity and mortality in tICH. This first prospective, randomized, placebo-controlled, dose-escalation study evaluated the safety and preliminary effectiveness of rFVIIa to limit tICH progression. METHODS Patients were enrolled if they had tICH lesions of at least 2 ml on a baseline computed tomographic scan obtained within 6 hours of injury. rFVIIa or placebo was administered within 2. 5 hours of the baseline computed tomographic scan but no later than 7 hours after injury. Computed tomographic scans were repeated at 24 and 72 hours. Five escalating dose tiers were evaluated (40, 80, 120, 160, and 200 microg/kg rFVIIa). Clinical evaluations and adverse events were recorded until Day 15. RESULTS No significant differences were detected in mortality rate or number and type of adverse events among treatment groups. Asymptomatic deep vein thrombosis, detected on routinely performed ultrasound at Day 3, was observed more frequently in the combined rFVIIa treatment group (placebo, 3%; rFVIIa, 8%; not significant). A nonsignificant trend for rFVIIa dose-response to limit tICH volume increase was observed (placebo, 21. 0 ml; rFVIIa, 10. 1 ml). CONCLUSION In this first prospective study of rFVIIa in tICH, there appeared to be less hematoma progression in rFVIIa-treated patients (80-200 microg/kg) compared with that seen in placebo treated patients. The potential significance of this biological effect on clinical outcomes and the significance of the somewhat higher incidence of ultrasound-detected deep vein thromboses in the rFVIIa-treated group need to be examined in a larger prospective randomized clinical trial.
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4.
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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5.
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.
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6.
Randomized, placebo-controlled, double-blind, multicenter phase III study to assess rFVIIa efficacy in acute intracerebral hemorrhage: the FAST trial
Steiner T, Mayer SA, Brun NC, Begtrup K, Broderick JP, Davis SM, Diringer MN, Skolnick BE
ISTH Congress. 2007;: Abstract No. O-S-006.
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7.
Determinants of intracerebral hemorrhage growth: an exploratory analysis
Broderick JP, Diringer MN, Hill MD, Brun NC, Mayer SA, Steiner T, Skolnick BE, Davis SM, Recombinant Activated Factor VIIIntracerebral Hemorrhage Trial Investigators
Stroke; a Journal of Cerebral Circulation. 2007;38((3):):1072-5.
Abstract
BACKGROUND AND PURPOSE We report an exploratory analysis from a randomized study of recombinant activated factor VII (rFVIIa) in patients with intracerebral hemorrhage (ICH) examining potential factors associated with hemorrhage growth. METHODS We explored the relationship between 5 different measures of change in hemorrhage volume between baseline and 24-hour CTs (absolute and percent change in ICH volume, ICH growth-categoric [no growth if change <33% and <12. 5 mL], absolute and percent change in ICH plus intraventricular hemorrhage [IVH] volume) and 31 demographic, clinical, imaging, historic, and baseline laboratory variables. Variables with a probability value of < or =0. 10 were included in the final multivariable models. RESULTS Treatment with rFVIIa and a longer time-from-onset-to-baseline CT were related to a decrease in hemorrhage growth in all 5 models. ICH volume on baseline CT was consistently associated with ICH growth in the various models. Other variables significantly related to growth of ICH or ICH+IVH in at least 1 of the 5 models include serum glucose (increased levels associated with increased growth), body mass index (heavier people have less growth), prior use of antiplatelet agent (prior use associated with increased growth), serum cholesterol (higher level associated with less hemorrhage growth), and serum creatinine (higher level associated with more hemorrhage growth). CONCLUSIONS Our exploratory analyses confirm that treatment with rFVIIa limits ICH growth in subjects with spontaneous ICH who met the criteria for this study. Most hematoma growth occurs early after onset of ICH. Larger hematomas on the baseline CT were associated with increased absolute ICH growth. The relationship of other factors to hemorrhage growth warrants further study.
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Dynamics of intraventricular hemorrhage in patients with spontaneous intracerebral hemorrhage: risk factors, clinical impact, and effect of hemostatic therapy with recombinant activated factor VII
Steiner T, Diringer MN, Schneider D, Mayer SA, Begtrup K, Broderick J, Skolnick BE, Davis SM
Neurosurgery. 2006;59((4):):767-73; discussion 773-4.
Abstract
OBJECTIVE To evaluate predictors of intraventricular hemorrhage (IVH) and IVH growth, impact of IVH growth on outcome, and impact of recombinant activated factor VII (rFVIIa) in patients with intracerebral hemorrhage (ICH). METHODS We analyzed 374 patients out of 399 who were randomized to rFVIIa (40, 80, or 160 mug/kg) or placebo for ICH (diagnosed within 3 h of symptoms). Risk factors for IVH growth (>2 ml increase in IVH volume at 24 h), and death or severe disability (modified Rankin scale score 4-6) at 3 months were identified (logistic regression). RESULTS IVH was present in 38% (n = 141) of patients at baseline and 45% (n = 169) by 24 hours. IVH growth, by 24 hours, occurred in 17 and 10% of placebo- and rFVIIa-treated patients, respectively (P = 0. 037). Risk factors for IVH growth included baseline mean arterial pressure greater than 120 mmHg, larger baseline ICH volume, IVH present at baseline, shorter time from symptom onset to baseline computed tomographic scan, and treatment (rFVIIa versus placebo) (all, P < or = 0. 037). Predictors of death or severe disability included older age, lower baseline Glasgow Coma Score, larger baseline ICH volume, IVH growth greater than 2 ml, IVH present at baseline or 24 hours, and treatment (rFVIIa versus placebo) (all, P < or = 0. 0405). CONCLUSION Presence of IVH at any time and early IVH growth worsen clinical outcome and increase mortality. Elevated mean arterial pressure at baseline may be a modifiable risk factor for IVH growth. Beneficial effects of rFVIIa on ICH outcome may be mediated, at least in part, by reducing IVH growth.
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Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial
Mayer SA, Brun NC, Broderick J, Davis SM, Diringer MN, Skolnick BE, Steiner T, United States NovoSeven ICHTrial Investigators
Neurocritical Care. 2006;4((3):):206-14.
Abstract
BACKGROUND AND PURPOSE Ultra-early hemostatic therapy may improve outcome after intracerebral hemorrhage (ICH) by preventing rebleeding and hematoma expansion. We conducted this trial to evaluate the safety of activated recombinant factor VII (rFVIIa; NovoSeven) for preventing early hematoma growth in acute ICH. METHODS In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial, 40 patients diagnosed with ICH by computed tomography within 3 hours of onset were treated with placebo or 5, 20, 40, or 80 microg/kg of rFVIIa ( n = 8 per group). Patients with any history of thromboembolic or vaso-occlusive disease were excluded. The primary endpoint was the frequency of adverse events (AEs). RESULTS Mean age was 65 years (range 34 - 91) and the median admission Glasgow Coma Scale score was 14. 5 (range 6 to 15). Mean ICH volume was 17 +/- 19 mL; nearly three-quarters were located in the basal ganglia ( n = 29). The mean interval from onset to treatment was 178 +/- 41 minutes. Thirty-three patients experienced 186 AEs, which occurred with similar frequency in the five groups. There were 10 thromboembolic AEs, including one case of deep vein thrombosis (20 microg g/kg group); one case of cerebral infarction (placebo); two cases of pulmonary embolism (20 and 40 microg g/kg groups); and six instances of ischemic ECG changes or cardiac enzyme elevation (placebo [ n = 2], 20 microg g/kg [ n = 1], 40 microg g/kg [ n = 1], and 80 microg g/kg [ n = 2] groups). No consumption coagulopathy or dose-related increase in edema-to-ICH volume ratio occurred. CONCLUSIONS Ultra-early rFVIIa treatment for ICH was associated with a reasonable safety profile in this preliminary study across a wide range of dosages. Further research is warranted to investigate the safety and potential efficacy of rFVIIa for minimizing ICH growth.
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10.
Recombinant activated factor VII for acute intracerebral hemorrhage
Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T, Recombinant Activated Factor VIIIntracerebral Hemorrhage Trial Investigators
The New England Journal of Medicine. 2005;352((8):):777-85.
Abstract
BACKGROUND Intracerebral hemorrhage is the least treatable form of stroke and is associated with high mortality. Among patients who undergo computed tomography (CT) within three hours after the onset of intracerebral hemorrhage, one third have an increase in the volume of the hematoma related to subsequent bleeding. We sought to determine whether recombinant activated factor VII (rFVIIa) can reduce hematoma growth after intracerebral hemorrhage. METHODS We randomly assigned 399 patients with intracerebral hemorrhage diagnosed by CT within three hours after onset to receive placebo (96 patients) or 40 microg of rFVIIa per kilogram of body weight (108 patients), 80 microg per kilogram (92 patients), or 160 microg per kilogram (103 patients) within one hour after the baseline scan. The primary outcome measure was the percent change in the volume of the intracerebral hemorrhage at 24 hours. Clinical outcomes were assessed at 90 days. RESULTS Hematoma volume increased more in the placebo group than in the rFVIIa groups. The mean increase was 29 percent in the placebo group, as compared with 16 percent, 14 percent, and 11 percent in the groups given 40 microg, 80 microg, and 160 microg of rFVIIa per kilogram, respectively (P=0. 01 for the comparison of the three rFVIIa groups with the placebo group). Growth in the volume of intracerebral hemorrhage was reduced by 3. 3 ml, 4. 5 ml, and 5. 8 ml in the three treatment groups, as compared with that in the placebo group (P=0. 01). Sixty-nine percent of placebo-treated patients died or were severely disabled (as defined by a modified Rankin Scale score of 4 to 6), as compared with 55 percent, 49 percent, and 54 percent of the patients who were given 40, 80, and 160 microg of rFVIIa, respectively (P=0. 004 for the comparison of the three rFVIIa groups with the placebo group). Mortality at 90 days was 29 percent for patients who received placebo, as compared with 18 percent in the three rFVIIa groups combined (P=0. 02). Serious thromboembolic adverse events, mainly myocardial or cerebral infarction, occurred in 7 percent of rFVIIa-treated patients, as compared with 2 percent of those given placebo (P=0. 12). CONCLUSIONS Treatment with rFVIIa within four hours after the onset of intracerebral hemorrhage limits the growth of the hematoma, reduces mortality, and improves functional outcomes at 90 days, despite a small increase in the frequency of thromboembolic adverse events.