Recombinant activated factor VII for acute intracerebral hemorrhage US phase IIA trial
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Background and Purpose
Ultra-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.
In 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).
Mean 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.
Ultra-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.
- Sacco RL, Mayer SA. Epidemiology of intracerebral hemorrhage. In: Felmann E, ed., Intracerebral Hemorrhage. Armonk, NY: Futura Publishing Co., 1994:3–23.
- Anderson CS, Chakera TM, Stewart-Wynne EG, Jamrozik KD. Spectrum of primary intracerebral haemorrhage in Perth, Western Australia, 1989–90: incidence and outcome. J Neurol Neurosurg Psychiatry 1994;57:936–940.
- Counsell C, Boonyakarnkul S, Dennis M, et al. Primary intracerebral hemorrhage in the Oxfordshire community stroke project, 2: prognosis. Cerebrovasc Dis 1995;5:26–34.
- Broderick JP, Adams HP Jr, Barsan W, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1999; 30:905–915.
- Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 2005;365:387–397.
- Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke 1993;24:987–993.
- Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28:1–5.
- Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke 1998;29:1160–1166.
- Fujii Y, Tanaka R, Takeuchi S, Koike T, Minakawa T, Sasaki O. Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg 1994;80:51–57.
- Fujitsu K, Muramoto M, Ikeda Y, Inada Y, Kim I, Kuwabara T. Indications for surgical treatment of putaminal hemorrhage: Comparative study based on serial CT and time-course analysis. J Neurosurg 1990;73:518–525.
- Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke 1996;27:1783–1787.
- Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke 2003;34:224–229. CrossRef
- Hedner U. NovoSeven® as a universal haemostatic agent. Blood Coagul Fibrinolysis 2000;11(Suppl 1):S107-S111.
- Friederich PW, Henny CP, Messelink EJ, et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomized trial. Lancet 2003;361:201–205. CrossRef
- Karadimov D, Binev K, Nachkov Y, Platikanov V. Use of activated recombinant factor VII (NovoSeven) during neurosurgery. J Neurosurg Anesthesiol 2003;15:330–332. CrossRef
- Park P, Fewel ME, Garton HJ, Thompson BG, Hoff JT. Recombinant activated factor VII for the rapid correction of coagulopathy in nonhemophilic neurosurgical patients. Neurosurgery 2003;53:34–39. CrossRef
- Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777–785. CrossRef
- Mayer SA, Brun NC, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T, for the Europe/Australasia NovoSeven ICH Trial Investigators. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke 2005;36:74–79. CrossRef
- Boeer A, Voth E, Henze T, Prange HW. Early heparin therapy in patients with spontaneous intracerebral hemorrhage. J Neurol Neurosurg Psychiatry 1991;54:466–467. CrossRef
- Lee KR, Colon GP, Betz AL, Keep RF, Kim S, Hoff JT. Edema from intracerebral hemorrhae: the role of thrombin. J Neurosurg 1996;84:91–96.
- Xi G, Keep RE, Hoff JT. Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 1998;89:991–996. CrossRef
- Roberts HR, Monroe DM 3rd, Hoffman M. Safety profile of recombinant factor VIIa. Semin Hematol 2004;41(Suppl 1): 101–108. CrossRef
- Macik BG, Lindley CM, Lusher J. Safety and initial clinical efficacy of three dose levels of recombinant activated factor VII (rFVIIa): results of a phase I study. Blood Coagul Fibrinolysis 1993;4:521–527. CrossRef
- Erhardtsen E, Nony P, Dechavanne M, Ffrench P, Boissel JP, Hedner U. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul Fibrinolysis 1998; 9:741–748. CrossRef
- Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997;99:542–547. CrossRef
- Mayer SA, Brun NC, Broderick J, Davis S, Diringer MN, Steiner T, for the NovoSeven ICH Trial Investigators. Predictors and clinical impact of hematoma growth in the Novoseven ICH Trial. Eur J Neurol 2004;11(suppl 2):367.[abstract]
- Recombinant activated factor VII for acute intracerebral hemorrhage US phase IIA trial
Volume 4, Issue 3 , pp 206-214
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- Humana Press
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- Intracerebral hemorrhage
- recombinant activated factor VII
- emergency stroke treatment
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- Author Affiliations
- 1. Departments of Neurology and Neurosurgery, Columbia University College of Physicians & Surgeons, New York, NY
- 3. Novo Nordisk A/S, Bagsaerd, Denmark
- 4. The University Of Cincinnati Medical Center, Cincinatti, OH
- 5. Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
- 6. Washington University School of Medicine, St. Louis, MO
- 7. Novo Nordisk, Princeton, NJ
- 8. University of Heidelberg, Heidelberg, Germany