Mar. 7, 2005 A new multi-center, international study led by Columbia University Medical Center researchers at NewYork-Presbyterian Hospital/Columbia shows that recombinant activated factor VII (rFVIIa) has the potential to be a significant advance in treating bleeding stroke (acute intracerebral hemorrhage or ICH). Published in the New England Journal of Medicine (Feb. 24 issue), the study found a reduction in hematoma growth (bleeding in the brain), decreased mortality, and improvement in neurological and clinical outcomes in patients treated with rFVIIa compared to placebo.
ICH is the deadliest and most disabling type of stroke – more than one out of three ICH patients die within one month of onset and only 20% regain functional independence. Physicians have long been frustrated by a lack of effective therapies to improve survival outcomes or recovery – current options are only supportive. RFVIIa is currently entering phase III trials as an investigational treatment for ICH. If approved by the U.S. Food and Drug Administration, it will become only the second emergency treatment for stroke in more than three decades – the first was TPA, approved by the FDA in 1996.
"Current medical and surgical options for ICH are not effective. Thirty-five to 50 percent of patients die within one month and if they survive, they live with serious neurological deficits. Current data suggest a possible change in our paradigm for the treatment of ICH," said Stephan A. Mayer, M.D., principal investigator of the study. Dr. Mayer is an associate professor of neurology and neurosurgery at Columbia University College of Physicians and Surgeons, and director of the Neurological Intensive Care Unit at NewYork-Presbyterian Hospital/Columbia.
"I approached this study with modest expectations, expecting to see some trends toward improved outcomes," noted Dr. Mayer. "I was stunned to find that by preventing just 5 ml of additional blood – about one teaspoon – of bleeding in the brain, we were able to increase chances of patient survival by nearly 40%." The third highest cause of death in the United States, stroke is the leading source of permanent disability – resulting in significant worsening of quality of life for patients and costing billions of dollars to society. ICH affects 15% of all stroke victims in the U.S., about 70,000 cases a year. In other parts of the world the incidence of bleeding stroke is even higher--in Asia, ICH affects 30% of all stroke victims.
With 73 sites in 20 countries, this study represents the largest clinical trial ever conducted with a pharmacologic agent for the treatment of ICH. As a physician treating patients over many years with this deadly form of stroke, Dr. Mayer decided to investigate rFVIIa as a treatment for ICH after reading about its coagulation effects. With the brand name NovoSeven®, rFVIIa has been on the U.S. market since 1999 as a treatment for hemophilia, and is manufactured by Novo Nordisk®.
Preliminary results of this trial were initially presented at the Fifth World Stroke Congress in Vancouver, B.C. in June 2004 and, most recently, at the International Stroke Conference in New Orleans in February 2005.
The trial included 399 patients who all underwent a CT scan to confirm they had ICH within three hours of onset. Patients were randomly assigned to receive placebo (N=96), 40 (N=108), 80 (N=92), or 160 (N=103) µg/kg doses of rFVIIa within one hour of the baseline scan. The trial results showed that treatment of ICH with rFVIIa within four hours of symptom onset reduced mortality and improved three-month clinical outcome, along with the reduction in hematoma growth, despite a greater frequency of thromboembolic events.
The primary endpoint of the study was to determine if recombinant activated factor VII (rFVIIa) could reduce hematoma growth after ICH. The primary outcome measure was the percent change in ICH volume at 24 hours. Clinical outcomes were assessed at 90 days. Key findings include:
* After dosing, the size of bleeding in the brain was assessed via CT scan within the first day and again three days later. Results found that overall, rFVIIa-treated patients had approximately half the amount of additional bleeding in the brain compared to placebo-treated patients.
* ICH volume growth in the 40, 80, and 160 µg/kg treatment groups (P=0.01, rFVIIa vs. placebo) was reduced by 45%, 52% and 62% compared to the placebo treatment group.
* After 90 days, results found a 38% reduction in mortality and up to three times as many patients surviving with no major neurological deficits, compared to placebo.
* The proportion of patients treated with the 160 µg/kg dose of rFVIIa with no disability was 24%, compared to 8% in placebo.
* Also after 90 days, there was a 16% absolute reduction in cases of death or severe disability among the rFVIIa treated patients.
* This indicates that for approximately every six patients treated, one case of death or severe disability was avoided.
* Safety endpoint: The overall frequency of fatal or disabling thromboembolic serious adverse events did not differ between the rFVIIa (2%) and the placebo (2%) groups. However, arterial thromboembolic serious adverse events occurred statistically significantly more frequently with rFVIIa treatment (5%) than with placebo (0%), manifesting in the form of myocardial ischemic events and cerebral infarction. The majority of patients recovered from these complications.
Columbia University Medical Center's Department of Neurology is one of the largest in the country, and is internationally recognized for pioneering research in the development of new treatment modalities and protocols for stroke. Columbia researchers recently won a highly competitive $12 million stroke center grant from the NIH. Columbia is the first site in the eastern United States to receive this Specialized Programs of Translational Research in Acute Stroke (SPOTRIAS) grant. Extending over five years, the funding will support three new research projects: one of the first clinical trials of statin medications as a potential stroke treatment; an imaging study of brain reorganization caused by stroke; and a novel stroke educational and behavior modification program.
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, medical education, and health care. The medical center trains future leaders in health care and includes the dedicated work of many physicians, scientists, nurses, dentists, and other health professionals at the College of Physicians & Surgeons, the School of Dental & Oral Surgery, the School of Nursing, the Mailman School of Public Health, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. With a strong history of some of the most important advances and discoveries in health care, its researchers are leading the development of novel therapies and advances to address a wide range of health conditions.
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