Abstract & Commentary
Commentary by Andrew D. Perron, MD, FACEP, FACSM, Residency Program Director, Department of Emergency Medicine, Maine Medical Center, Portland, ME. Dr. Perron is on the Editorial Board of Emergency Medicine Alert.
Source: Mayer SA, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005; 352:777-785.
Intracerebral hemorrhage (ICH), while relatively rare, is the least treatable form of stroke and the one with the highest associated mortality. Previous studies have linked outcome (at least in part) to the size of the hemorrhage. Further, other studies have shown that approximately a third of these cases will demonstrate an increase in the volume of the hemorrhage within the three hours subsequent to the original event. Therefore, it can be hypothesized, as these authors have done, that if there were a way to prevent this continued growth of the ICH, the outcome could be improved.
This study, sponsored by Novo Nordisk Inc., sought to determine if recombinant factor VIIa (rFVIIa, trade name NovoSeven) could inhibit hematoma growth in patients with ICH, and consequently improve morbidity within this patient population. This prospective, randomized, double-blind, and placebo-controlled study enrolled 399 patients into one of four treatment arms following identification of ICH on a cranial computerized tomography (CT) scan. The study arms included placebo (96 patients), and three different treatment arms (doses of 40, 80, or 160 mcg/kg rFVIIa). The primary outcome assessed was percent change in ICH volume at 24 hours. The secondary outcome measure was clinical outcome at 90 days. Note that patients with coagulopathy were not included in this study (stated exclusion criteria).
The reported findings of the study were reduced hematoma volume growth of 16%, 14%, and 11% in the three treatment arms vs 29% with placebo. Mortality was reduced by 38% for rFVIIa-treated patients vs placebo. Overall, the authors report a 16% absolute reduction in the risk of death or severe disability at three months.
One important safety point also was noted in this trial. While the frequencies of fatal or disabling thromboembolic serious adverse events were the same in the placebo and treatment arms (2%), a statistically significant increase was noted in the treatment arm for serious thromboembolic events (myocardial infarction and cerebrovascular accident)—5% with rFVIIa vs 0% for placebo. Notably, exclusion criteria had to be changed during this study due to safety concerns to exclude patients with any history of thrombotic or vaso-occlusive disease.
Commentary
Hemorrhagic stroke treatment in the ED has been relatively straightforward to this point (although not necessarily fruitful). Interventions have been limited to airway control, blood pressure modulation, and correction of coagulopathy (if present) for the majority of these patients. Neurosurgical consultation may or may not result in operative evacuation of clot, depending upon patient factors such as location and size of bleed, Glasgow Coma Scale score, and co-morbidities.
The use of rFVIIa, currently marketed for treatment of hemophilia, as a potential therapeutic intervention in ICH raises the possibility of an additional weapon for the emergency physician in the treatment of this disease. If this study bears-out, this could mean a decrease in morbidity and mortality in ICH. So the $64,000 question is: Where do we go from here? As the article’s accompanying editorial highlights, the findings of this study are potentially important, but not clinically directive at this point. The time window, as with non-hemorrhagic cerebrovascular accident, is relatively small (4 hours), and potentially will exclude many patients from treatment. In a further analogy to thrombolytics for thromboembolic cerebrovascular accident, the risks of treatment are not insignificant (myocardial infarction and cerebrovascular accident) and were prevalent enough in the study to cause the authors to change the exclusion criteria midstream.
Two other areas deserve discussion regarding rFVIIa and this study. The first is the noted high cost of this drug. I cannot find any cost data regarding use in this indication, but a study in hemophiliacs noted an incremental cost of $51,533 per quality-of-life-year for treatment.2 Clearly, a similar cost analysis needs to be performed on this indication to see what the incremental cost is associated with usage for ICH. Given the high cost of treatment and the patient population effected, I suspect this would not be a favorable result.
The second area of my concern is the depth of Novo Nordisk involvement in this study. Not only was this study completely funded by Novo Nordisk, but three of the eight listed investigators are company employees (and stockholders); the lead author receives separate research funding from it; five of the authors receive consulting fees from it; and four of the authors (including the lead author) receive lecture fees from the company. Before widespread acceptance of this treatment, I certainly would hope that an independent group could replicate the results.
References
1. Brown DL, et al. Stopping the bleeding in intracerebral hemorrhage. N Engl J Med 2005;352:828-830.
2. Ekert H, et al. Cost-utility analysis of recombinant factor VIIa (NovoSeven) in six children with long-standing inhibitors to factor VIII or IX. Haemophilia 2001; 7:279-285.
Intracerebral hemorrhage (ICH), while relatively rare, is the least treatable form of stroke and the one with the highest associated mortality.
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