Nikolai C. Brun

Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage

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].).

Determinants of Intracerebral Hemorrhage Growth. An Exploratory Analysis

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 ≤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.

Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage

Background and Purpose— Hematoma growth occurs in 38% of intracerebral hemorrhage (ICH) patients scanned by computed tomography (CT) within 3 hours of onset. Activated recombinant factor VII (rFVIIa) promotes hemostasis at sites of vascular injury and may minimize hematoma growth after ICH. Methods— In this randomized, double-blind, placebo-controlled, dose-escalation trial, 48 subjects with ICH diagnosed within 3 hours of onset were treated with placebo (n=12) or rFVIIa (10, 20, 40, 80, 120, or 160 &mgr;g/kg; n=6 per group). The primary endpoint was the frequency of adverse events (AEs). Safety assessments included serial electrocardiography (ECG), troponin I and coagulation testing, lower extremity Doppler ultrasonography, and calculation of edema:ICH volume ratios. Results— Mean age was 61 years (range, 30 to 93) and 57% were male. At admission, mean National Institutes of Health Stroke Scale (NIHSS) score was 14 (range, 1 to 26), median Glasgow Coma Scale score was 14 (range, 6 to 15), and mean ICH volume was 21 mL (range, 1 to 151). Mean time from onset to treatment was 181 minutes (range, 120 to 265). Twelve serious AEs occurred, including 5 deaths (mortality 11%). Six AEs were considered possibly treatment-related, including rash, vomiting, fever, ECG T-wave inversion, and 2 cases of deep vein thrombosis (placebo and 20-&mgr;g/kg groups). No myocardial ischemia, consumption coagulopathy, or dose-related increase in edema:ICH volume occurred. Conclusion— This small phase II trial evaluated a wide range of rFVIIa doses in acute ICH and raised no major safety concerns. Larger studies are justified to determine whether rFVIIa can safely and effectively limit ICH growth.

Can a Subset of Intracerebral Hemorrhage Patients Benefit From Hemostatic Therapy With Recombinant Activated Factor VII

Background and Purpose— In the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial, 80 &mgr;g/kg of recombinant activated factor VII (rFVIIa) significantly reduced intracerebral hemorrhage (ICH) expansion when given within 4 hours of onset. However, in contrast to an earlier Phase 2b study, rFVIIa did not improve survival or functional outcome. In this exploratory analysis, we hypothesized that earlier treatment and exclusion of patients with a poor prognosis at baseline might enhance the benefit of rFVIIa treatment. Methods— Using the FAST data set, the impact of rFVIIa (80 &mgr;g/kg) on poor outcome at 3 months (modified Rankin Score of 5 or 6) was systematically evaluated within subgroups using clinically meaningful cut points in onset-to-treatment time, age, and baseline ICH and intraventricular hemorrhage volume. The effect of treatment on outcome was analyzed using logistic regression, and ICH volume was analyzed with linear mixed models. Results— A subgroup (n=160, 19% of the FAST population) was identified comprising patients ≤70 years with baseline ICH volume <60 mL, intraventricular hemorrhage volume <5 mL, and time from onset-to-treatment ≤2.5 hours. The adjusted ORs for poor outcome with rFVIIa treatment was 0.28 (95% CI, 0.08 to 1.06), whereas the reduction in ICH growth was almost doubled (7.3±3.2 versus 3.8±1.5 mL, P=0.02). The improved effect was confirmed in an analysis of similar Phase 2 patients. Conclusions— A prospective trial would be needed to determine whether younger patients with ICH without extensive bleeding at baseline can benefit from 80 &mgr;g/kg of rFVIIa given within 2.5 hours of symptom onset.

Thromboembolic Events With Recombinant Activated Factor VII in Spontaneous Intracerebral Hemorrhage Results From the Factor Seven for Acute Hemorrhagic Stroke (FAST) Trial

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 &mgr;g/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-&mgr;g/kg group, and 82 (46%) in the 80 &mgr;g/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 &mgr;g/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 &mgr;g/kg, and 80-&mgr;g/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.

Recombinant activated factor VII for acute intracerebral hemorrhage US phase IIA trial

Background and PurposeUltra-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.MethodsIn 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 μg/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).ResultsMean 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 μg/kg group); one case of cerebral infarction (placebo); two cases of pulmonary embolism (20 and 40 μg/kg groups); and six instances of ischemic ECG changes or cardiac enzyme elevation (placebo [n=2], 20 μg/kg [n=1], 40 μg/kg [n=1], and 80 μg/kg [n=2] groups). No consumption coagulopathy or dose-related increase in edema-to-ICH volume ratio occurred.ConclusionsUltra-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.

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 &mgr;g/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 &mgr;g/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 &mgr;g/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.

Impact of recombinant activated factor VII on health-related quality of life after intracerebral hemorrhage.

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 µg/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.

Timing Is Everything in Intracerebral Hemorrhage

To the Editor: Hallevi and coworkers recently reported on the off-label use of rFVIIa in 46 patients with ICH.1 Twenty-four patients received rFVIIa within 3 hours, and 22 within 3 to 4 hours. Volume increase and outcome at discharge were compared with 148 historical controls. The authors did not find a difference in reduction of volume increase between the 0 to 3 and the 3 to 4 hour group. Nor did they find a difference in outcome between the factor VIIa treated and the control patients. They conclude that timing of hemostatic therapy may not have an influence on volume reduction or outcome in ICH patients. We are not as quick to agree with this conclusion, for the following reasons: First, mean volumes were remarkably smaller—only one-third—than volumes that were found in FAST.2 Size of …