Early recombinant activated factor VII for intracerebral hemorrhage reduced hematoma growth and mortality, while improving functional outcomes

Abstract

Expanded AbstractCitationMayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T: Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005, 352:777–785 [1].HypothesisRecombinant activated factor VIIa (rFVIIa) can effectively reduce hematoma growth and improve outcomes when given within 4 hours of symptom onset in patients with acute intracerebral hemorrhage.MethodsDesignInternational multi-center randomized placebo-controlled trial.SettingEmergency departments and intensive care units in 73 hospitals in 20 countries.Subjects399 adults age 18 years or older with spontaneous intracerebral hemorrhage documented by CT scanning within 3 hours of onset of symptoms. Exclusion criteria included a score of 3 to 5 on the Glasgow Coma Scale (indicating deep coma); planned surgical evacuation of hematoma within 24 hours after admission; secondary intracerebral hemorrhage related to aneurysm, arteriovenous malformation, trauma, or other causes; known use of oral anticoagulant agents; known thrombocytopenia; history of coagulopathy, acute sepsis, crush injury, or disseminated intravascular coagulation; pregnancy; preexisting disability; and symptomatic thrombotic or vaso-occlusive disease within 30 days before the onset of symptoms of intracerebral hemorrhage. Midway through the trial, the last criterion was amended to exclude patients with any history of thrombotic or vaso-occlusive disease.InterventionPatients were randomly assigned to receive a single intravenous dose of 40 μg, 80 μg, or 160 μg per kilogram of rFVIIa (NovoSeven, Novo Nordisk) or placebo. Treatment was given within one hour after the baseline CT and no later than four hours the symptom onset.OutcomesThe primary outcome was percent change in volume of intracerebral hemorrhage at 24 hours. Secondary outcomes included 90-day mortality and functional status.ResultsHematoma 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 μg, 80 μg, and 160 μg 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). At 90 days, 69% 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 μg 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).ConclusionTreatment 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.