Kamilla Begtrup

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.

BACKGROUND: Although volume of intracerebral hemorrhage (ICH) is a predictor of mortality, it is unknown whether subsequent hematoma growth further increases the risk of death or poor functional outcome. METHODS: To determine if hematoma growth independently predicts poor outcome, the authors performed an individual meta-analysis of patients with spontaneous ICH who had CT within 3 hours of onset and 24-hour follow-up. Placebo patients were pooled from three trials investigating dosing, safety, and efficacy of rFVIIa (n = 115), and 103 patients from the Cincinnati study (total 218). Other baseline factors included age, gender, blood glucose, blood pressure, Glasgow Coma Score (GCS), intraventricular hemorrhage (IVH), and location. RESULTS: Overall, 72.9% of patients exhibited some degree of hematoma growth. Percentage hematoma growth (hazard ratio [HR] 1.05 per 10% increase [95% CI: 1.03, 1.08; p < 0.0001]), initial ICH volume (HR 1.01 per mL [95% CI: 1.00, 1.02; p = 0.003]), GCS (HR 0.88 [95% CI: 0.81, 0.96; p = 0.003]), and IVH (HR 2.23 [95% CI: 1.25, 3.98; p = 0.007]) were all associated with increased mortality. Percentage growth (cumulative OR 0.84 [95% CI: 0.75, 0.92; p < 0.0001]), initial ICH volume (cumulative OR 0.94 [95% CI: 0.91, 0.97; p < 0.0001]), GCS (cumulative OR 1.46 [95% CI: 1.21, 1.82; p < 0.0001]), and age (cumulative OR 0.95 [95% CI: 0.92, 0.98; p = 0.0009]) predicted outcome modified Rankin Scale. Gender, location, blood glucose, and blood pressure did not predict outcomes. CONCLUSIONS: Hematoma growth is an independent determinant of both mortality and functional outcome after intracerebral hemorrhage. Attenuation of growth is an important therapeutic strategy.

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.

OBJECTIVE: The requirement to inject current basal insulin analogs at a fixed time each day may complicate adherence and compromise glycemic control. This trial evaluated the efficacy and safety of varying the daily injection time of insulin degludec (IDeg), an ultra-long-acting basal insulin. RESEARCH DESIGN AND METHODS: This 26-week, open-label, treat-to-target trial enrolled adults (≥18 years) with type 2 diabetes who were either insulin naïve and receiving oral antidiabetic drugs (OADs) (HbA(1c) = 7-11%) or previously on basal insulin ± OAD(s) (HbA(1c) = 7-10%). Participants were randomized to 1) once-daily (OD) IDeg in a prespecified dosing schedule, creating 8-40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily insulin glargine at the same time each day (IGlar OD; n = 230). The primary outcome was noninferiority of IDeg OD Flex to IGlar OD in HbA(1c) reduction after 26 weeks. RESULTS: After 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA(1c) by 1.28, 1.07, and 1.26% points, respectively (estimated treatment difference [IDeg OD Flex - IGlar OD]: 0.04% points [-0.12 to 0.20], confirming noninferiority). No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups. CONCLUSIONS: The use of extreme dosing intervals of 8-40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety.