Stephan A. Mayer

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].).

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.

OBJECTIVE: To identify patients most likely to have seizures documented on continuous EEG (cEEG) monitoring and patients who require more prolonged cEEG to record the first seizure. METHODS: Five hundred seventy consecutive patients who underwent cEEG monitoring over a 6.5-year period were reviewed for the detection of subclinical seizures or evaluation of unexplained decrease in level of consciousness. Baseline demographic, clinical, and EEG findings were recorded and a multivariate logistic regression analysis performed to identify factors associated with 1) any EEG seizure activity and 2) first seizure detected after >24 hours of monitoring. RESULTS: Seizures were detected in 19% (n = 110) of patients who underwent cEEG monitoring; the seizures were exclusively nonconvulsive in 92% (n = 101) of these patients. Among patients with seizures, 89% (n = 98) were in intensive care units at the time of monitoring. Electrographic seizures were associated with coma (odds ratio [OR] 7.7, 95% CI 4.2 to 14.2), age <18 years (OR 6.7, 95% CI 2.8 to 16.2), a history of epilepsy (OR 2.7, 95% CI 1.3 to 5.5), and convulsive seizures during the current illness prior to monitoring (OR 2.4, 95% CI 1.4 to 4.3). Seizures were detected within the first 24 hours of cEEG monitoring in 88% of all patients who would eventually have seizures detected by cEEG. In another 5% (n = 6), the first seizure was recorded on monitoring day 2, and in 7% (n = 8), the first seizure was detected after 48 hours of monitoring. Comatose patients were more likely to have their first seizure recorded after >24 hours of monitoring (20% vs 5% of noncomatose patients; OR 4.5, p = 0.018). CONCLUSIONS: CEEG monitoring detected seizure activity in 19% of patients, and the seizures were almost always nonconvulsive. Coma, age <18 years, a history of epilepsy, and convulsive seizures prior to monitoring were risk factors for electrographic seizures. Comatose patients frequently required >24 hours of monitoring to detect the first electrographic seizure.

Intracerebral hemorrhage is the least treatable form of stroke and is associated with 30% to 50% mortality rate. Early hematoma growth occurs in 18% to 38% of patients scanned within 3 hours of intracerebral hemorrhage onset, and hematoma volume is an important predictor of poor outcome. Recombinant activated factor VII, a potent initiator of hemostasis, is currently approved for the treatment of bleeding in hemophilia patients with inhibitors and has also been shown to promote hemostasis in patients with normal coagulation. A recent phase IIB randomized, double-blind, placebo-controlled, dose-ranging "proof-of-concept" trial enrolled 399 intracerebral hemorrhage patients to determine whether recombinant activated factor VII can limit ongoing bleeding and improve outcome. An approximate 50% relative reduction in hematoma growth was evident with all 3 doses that were tested (40, 80, and 160 microg/kg), which translated into an average reduction in absolute intracerebral hemorrhage volume growth of approximately 5 milliliters. More importantly, recombinant activated factor VII was associated with a 38% relative reduction in mortality and significantly improved functional outcome among survivors, despite a 5% frequency of arterial thromboembolic events (primarily ischemic stroke and myocardial infarction). A large phase III trial (the FAST trial [Factor Seven for Acute Hemorrhagic Stroke Treatment]) is now in progress to confirm these findings.

OBJECTIVE: We developed a modification of the Fisher computed tomographic rating scale and compared it with the original Fisher scale to determine which scale best predicts symptomatic vasospasm after subarachnoid hemorrhage. METHODS: We analyzed data from 1355 subarachnoid hemorrhage patients in the placebo arm of four randomized, double-blind, placebo-controlled studies of tirilazad. Modified Fisher computed tomographic grades were calculated on the basis of the presence of cisternal blood and intraventricular hemorrhage. Crude odds ratios (OR) reflecting the risk of developing symptomatic vasospasm were calculated for each scale level, and adjusted ORs expressing the incremental risk were calculated after controlling for known predictors of vasospasm. RESULTS: Of 1355 patients, 451 (33%) developed symptomatic vasospasm. For the modified Fisher scale, compared with Grade 0 to 1 patients, the crude OR for vasospasm was 1.6 (95% confidence interval [CI], 1.0-2.5) for Grade 2, 1.6 (95% CI, 1.1-2.2) for Grade 3, and 2.2 (95% CI, 1.6-3.1) for Grade 4. For the original Fisher scale, referenced to Grade 1, the OR for vasospasm was 1.3 (95% CI, 0.7-2.2) for Grade 2, 2.2 (95% CI, 1.4-3.5) for Grade 3, and 1.7 (95% CI, 1.0-3.0) for Grade 4. Early angiographic vasospasm, history of hypertension, neurological grade, and elevated admission mean arterial pressure were identified as risk factors for symptomatic vasospasm. After adjusting for these variables, the modified Fisher scale remained a significant predictor of vasospasm (adjusted OR, 1.28; 95% CI, 1.06-1.54), whereas the original Fisher scale was not. CONCLUSION: The modified Fisher scale, which accounts for thick cisternal and ventricular blood, predicts symptomatic vasospasm after subarachnoid hemorrhage more accurately than original Fisher scale.