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Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated

Abstract
Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated

Publication: N Engl J Med 2005;352:777-85.
Monday, March 7th, 2005

Author: Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T;

Article
Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T;

Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-85.

Design
Multicenter, prospective, randomized, double-blind, placebo-controlled, phase IIb, dose-ranging, proof-of-concept trial. Number of patients: 399. Setting: 73 medical centers in 20 countries. Study period: August 2002 – March 2004.

Overview

Background
Intracerebral hemorrhage (ICH) is the deadliest, most disenabling, and least treatable form of stroke. ICH is estimated to account for 10 to 15% of all strokes and to have a one-year mortality greater than 60%. Among patients who undergo computed tomography (CT) within three hours after the onset of ICH, one third have an increase in the volume of the hematoma related to subsequent bleeding. Ultra-early administration of hemostatic therapy in the emergency setting may improve outcome after ICH by stopping bleeding and minimizing hematoma growth and volume, a critical determinant of mortality and functional outcome. Recombinant factor VIIa (rFVIIa), which is approved in the US for the treatment of bleeding episodes in hemophilia patients with inhibitors to factor VIII or IX, has been successfully used to control ICH in patients with hemophilia or other coagulation disorders as well as in noncoagulopathic patients. In two recent dose-escalation safety studies, doses of rFVIIa ranging from 5 to 160 μg/kg were not associated with an increased risk of thromboembolic complications in patients with acute ICH. In this multicenter, prospective, randomized, double-blind, placebo-controlled trial, the authors evaluated the ability of rFVIIa to reduce hematoma growth and thus improve outcomes in patients with acute ICH.

Methods
The study was conducted between August 2002 and March 2004 at 73 medical centers in 20 countries. Patients were eligible for enrollment if they were over 18 years old and had spontaneous ICH documented by CT within 3 hours of symptom onset. Exclusion criteria included deep coma (Glasgow Coma Scale [GCS] 3-5) at time of admission, surgical hematoma evacuation planned or performed within 24 hours of admission, secondary ICH, known use of oral anticoagulant agents, known thrombocytopenia, a 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 ICH. Midway through the trial, because of concerns about safety, the last criterion was amended to exclude also patients with any history of thrombotic or vaso-occlusive disease.

Patients were randomized to receive a single intravenous dose of 40, 80, or 160 μg rFVIIa per kilogram of body weight, or placebo. Randomization was performed in blocks of four patients using sequentially-numbered, identical-appearing containers. Treatment was administered within one hour of the baseline CT scan and no later than four hours after the onset of the symptoms. Follow-up CT scanning was performed at 24 and 72 hours after treatment administration. CT data were transmitted to an imaging laboratory and analyzed in random order by two neuroradiologists blinded to treatment allocations, and the volumes of intracerebral hemorrhage, intraventricular hemorrhage, and edema were calculated with use of standard planimetric techniques. The primary efficacy endpoint was the change in the volume of intracerebral hemorrhage, expressed as a percentage, from baseline to 24 hours in the three rFVIIa-treatment groups as compared with the placebo group. This study was powered to detect a relative reduction of 56% in the growth of the hematoma (from 32% in the placebo group to 14% with active treatment) in any one of the three rFVIIa-treatment groups, as compared with placebo.

Results
A total of 399 patients completed the trial. Baseline characteritics were similar in the four study groups. The mean interval from the onset of symptoms to the baseline CT scan was 114 ± 35 minutes, from CT to treatment 54 ± 21 minutes, and from onset to treatment 167 ± 32 minutes. Baseline and 24-hour CT scans were obtained for 96% of all patients.

The mean percent increase in the volume of intracerebral hemorrhage was 29% in the placebo group and 16%, 14% and 11% in the groups given 40, 80 and 160 µg rFVIIa per kilogram, respectively. It was significantly lower in the group that received 160 µg of rFVIIa per kilogram, as well as in the combined rFVIIa groups, than in the placebo group (p < 0.0167, Bonferroni-corrected threshold), whereas the difference was not statistically significant for the groups given 40 µg and 80 µg per kilogram. The mean absolute increase of volume of intracerebral hemorrhage was also significantly smaller in the combined rFVIIa groups compared to placebo (4.2 vs. 8.7 mL) – a relative reduction of 52% – with a dose-response effect (p for trend = 0.007).

The percentage of patients who died or were severely disabled was 69% in the placebo group and higher compared to 55%, 49%, and 54% in the 40, 80, and 160 µg/kg rFVIIa groups, respectively (p = 0.004 for the comparison of the combined three rFVIIa groups with the placebo group). Mortality at three months was 29% in the placebo group, as compared with 18% in the combined rFVIIa-treatment groups, representing a relative reduction of 38% (p = 0.02, chi-square test). Thromboembolic serious adverse events occurred in 2% of the patients in the placebo group, compared with 7% of the patients administered rFVIIa (p = 0.12, Fisher’s exact test).

Conclusion
The authors conclude that ultra-early hemostatic therapy with rFVIIa limits the growth of hemorrhage, reduces mortality, and improves functional outcomes after intracerebral hemorrhage, but until additional data on safety are available rFVIIa should be administered with caution to patients with ICH who have risk factors for thromboembolic disease.



Key Points
• Intracerebral hemorrhage (ICH) is the deadliest, most disenabling, and least treatable form of stroke.
• Ultra-early administration of hemostatic therapy in the emergency setting may improve outcome after ICH by stopping bleeding and minimizing hematoma growth and volume, a critical determinant of mortality and functional outcome.
• In this multicenter, prospective, randomized, double-blind, placebo-controlled trial, the authors evaluated the ability of rFVIIa to reduce hematoma growth and thus improve outcomes in patients with acute ICH.
• Ultra-early hemostatic therapy with rFVIIa was found to limit the growth of hemorrhage, reduce mortality, and improve functional outcomes after ICH, despite a nonsignificant increase in the rate of throñboembolic events.


Limitations
• Study groups may not have been comparable as there was no adjustment for blood pressure, a possible determinant of outcomes in patients with ICH.
• The potential interaction between rFVII treatment and blood pressure was not assessed.
• There was no adjustment for the withdrawal of care, although the overall aggressiveness of care may influence clinical outcomes.


SABM Rating:*****

In Brief
In this much-awaited international, multicenter, randomized, double-blind, placebo-controlled trial, Dr. Mayer and co-authors evaluated the ability of ultra-early hemostatic therapy with rFVIIa to reduce hematoma growth in patients with acute ICH. rFVIIa administration within four hours of the onset of ICH was found to limit the growth of hemorrhage, reduce mortality, and improve functional outcomes after ICH. A nonsignificant increase in the rate of thromboembolic events was observed in patients given rFVIIa. “Beyond aggressive supportive care,� Drs. Brown and Morgenstern note in the accompanying editorial, “clinicians have not had specific treatments to offer patients with intracerebral hemorrhage.� The study by Mayer et al. therefore “offers new hope for targeted therapy for this frequent cause of neurologic disability and death.� However, they add, these results should be viewed as preliminary as the clinical experience with rFVIIa in this setting remains limited (especially with the highest and most effective dose, 160 µg per kilogram), and further information on the safety of this treatment will be needed before it can be recommended.

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