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 TOP Article appraised Structured abstractCommentary by M.A. Ewanchuk...References |
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Structured abstract |
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TOPArticle appraisedStructured abstractCommentary by M.A. Ewanchuk...References |
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Design: Multicentre, randomized, double-blind, placebo-controlled trial of three different doses of rFVIIa.
Setting: Seventy-three hospitals in 20 countries.
Patients: Three hundred and ninety-nine patients with computed tomographic (CT) scan-documented ICH within three hours of the onset of symptoms. Exclusion criteria included pregnancy; Glasgow Coma Scale score > 2; planned surgical evacuation within 24 hr; hemorrhage secondary to aneurysm, arteriovenous malformation, or trauma; use of oral anticoagulants; thrombocytopenia; preexisting coagulopathy or dis-seminated intravascular coagulation; crush injury; acute sepsis; a preexisting neurologic disability; or any history of symptomatic thrombotic or vaso-occlusive disease. Baseline characteristics were similar between groups.
Intervention: One hundred and eight, 92, and 103 patients were allocated to receive a single dose of 40 µg·kg–1, 80 µg·kg–1, or 160 µg·kg–1 rFVIIa respectively. Ninety-six patients were allocated to receive a placebo equivalent. The intervention was given within one hour of baseline CT, and no later than four hours after the onset of symptoms.
Main outcomes: The primary outcome was the percentage change in the volume of ICH from baseline to 24 hr on CT scan as analyzed by two neuroradiologists blinded to allocation. Secondary outcomes included the percentage change in volume of ICH from baseline to 72 hr, and scores from the Glasgow Coma Scale, the National Institutes of Health Stroke Scale, the modified Rankin Scale, the Extended Glasgow Outcome Scale, and the Barthel Index based on clinical assessments performed on days one, two, three, 15 and 90.
Main results: The mean increase in the hematoma volume was 29% in the placebo group, as compared to 16%, 14%, and 11% in the groups given 40, 80, and 160 µg·kg–1 rFVIIa, respectively. 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 (modified Rankin Scale score of 4-6), as compared to 55%, 49%, and 54% of the patients who received 40, 80, and 160 µg·kg–1 rFVIIa, respectively. There was a trend towards higher rates of serious thromboembolic adverse events (mainly myocardial or cerebral infarction) in the three treatment groups when compared to the placebo group (7% vs 2%, P = 0.12). Mortality at 90 days was 29% for patients who received placebo, as compared with 18% in the three rFVIIa groups combined (P = 0.02).
Conclusion: 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.
Funding: Novo Nordisk.
Correspondence: Dr. Stephen A. Mayer, Neurological Institute, 710 West 168th Street, Box 39, New York, NY, 10032 USA. E-mail: sam14{at}columbia.edu
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Commentary by M.A. Ewanchuk and D.A. Hudson |
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TOPArticle appraisedStructured abstractCommentary by M.A. Ewanchuk...References |
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Intracerebral hemorrhage is a devastating problem: 35 to 52% of patients are dead at one month, with only 20% living independently at six months. Worldwide incidences range from 10 to 20 per 100,000 population, and are expected to double in the next 50 years due to the aging population, and changing racial demographics.1 To date, clinicians have been powerless to intervene once bleeding occurs –38% of patients will have a subsequent increase in the volume of the hematoma on repeat CT scanning, even in the absence of coagulopathy.2 Progressive bleeding of this type has been shown to correlate with poor outcome, even after early (less than four hours) surgical clot evacuation.3
Recombinant factor VIIa promotes local hemostasis at sites of vascular injury in both normal and coagulopathic individuals. An open-label, uncontrolled, emergency-use study of rFVIIa has previously demonstrated efficacy in the treatment of ICH in patients with hemophilia A or B;4 more recently, a perioperative randomized controlled trial of rFVIIa has been shown to reduce blood loss in patients with normal coagulation systems.5 On the basis of these observations, early therapy with rFVIIa was hypothesized to reduce hematoma volumes and improve patient outcomes. Indeed, such was the finding of Mayer et al. in the present trial; however, it must be noted that the hemostatic effect of rFVIIa was only evident when the treatment was given within three hours after the onset of symptoms. Furthermore, the effect was dose-related, with the smallest effect at 40 µg·kg–1 and the largest at 160 µg·kg–1. Therapy with rFVIIa was deemed to be safe as the incidence of fatal or disabling thromboembolic adverse events that were "possibly or probably related to treatment" occurred in 2% of both placebo and rFVIIa-treated patients. But, as with all new interventions, the question must be asked: do the potential cost-savings in terms of days of institutionalization prevented (or the improved functional outcomes) truly justify the use of this potentially expensive therapy? Given a number-needed-to-treat of six, we must await future cost-benefit analysis data. A large multicentre trial is underway currently. In the end, rFVIIa appears to be a potent prohemostatic agent that shows promise in the treatment of life-threatening intracerebral bleeding in patients with complex coagulation disorders and those with normal coagulation profiles.6 However, given the relative inhomogenity of the patient population, the possibility of substantial adverse effects, and the potential lack of true benefit, widespread use of rFVIIa for this indication should not be encouraged at the present time.
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References |
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TOPArticle appraisedStructured abstractCommentary by M.A. Ewanchuk...References |
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2 Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997; 28: 1–5.
3 Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke 2003; 34: 224–9.
4 Arkin S, Cooper HA, Hutter JJ, et al. Activated recombinant human coagulation factor VII therapy for intra-cranial hemorrhage in patients with hemophilia A or B with inhibitors. Results of the novoseven emergency-use program. Haemostasis 1998; 28: 93–8.[Medline]
5 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 randomised trial. Lancet 2003; 361: 201–5.[Medline]
6 Levi M, Peters M, Buller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit Care Med 2005; 33: 883–90.[Medline]
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