The use of recombinant activated factor VIIa for acute cerebral hemorrhage and hemorrhage in trauma

Louise A. Prince, MD FACEP, Associate Professor, Emergency Medicine, SUNY Upstate Medical University

Many patients present to the Emergency Department with life threatening hemorrhage either from trauma or intracerebral bleeding. As our population matures in age, many patients are also on vitamin-K antagonists such as wafarin (coumadin) to treat chronic medical illnesses. Treatment of a life threatening hemorrhage in a patient who is anticoagulated on these medications in the past has consisted of the use of Vitamin K and fresh frozen plasma to reverse the effect of the medication. The onset of action of vitamin K is delayed and the time required to thaw fresh frozen plasma can be at least 45 minutes. In 2003 the journal Blood Coagulation and Fibrinolysis (1) published the first use of recombinant factor VIIa (rFVIIa) as additional therapy in seven patients presenting with central nervous system bleeding emergencies. They demonstrated a rapid reduction in the International Normalized Ratio (INR) after the administration of rFVIIa. All patients survived and did not experience any thromboembolic events. They also tested the use of rFVIIa on blood samples of 25 patients on stable life long anticoagulation. This testing also demonstrated similar rapid reduction of the INR value.

Following this publication, the use of rFVIIa in other patients with hemorrhage despite prior anticoagulation began to emerge. In 2005, The New England Journal of Medicine published “Recombinant Activated Factor VIIa for Acute Intracerebral Hemorrhage.” (2) 399 patients were randomly assigned to receive either placebo, 40 mcg/kg of rFVIIa, 80 mcg/kg of rFVIIa, or 160 mcg/kg of rFVIIa within one hour after baseline scan and within three hours after onset of hemorrhage. Patients who were anticoagulated previously were excluded from this study. The primary outcome measure was the percent change in the volume of the intracerebral hemorrhage at 24 hours. Hematoma volume increased more in the placebo group than in the rFVIIa groups. Mortality at 90 days was 29 percent for patients who received placebo and 18 percent in the three rFVIIa groups combined. Serious thromboembolic events occurred in seven percent of the rFVIIa treated patients, as compared to two percent of those given placebo.

Further research in the area of hemorrhage control in severely injured trauma patients has also demonstrated some benefit from the use of rFVIIa. The Journal of Trauma in July of 2005 outlined two studies which revealed improvement of hemorrhage control when rFVIIa was used as adjunctive therapy. The first (3), conducted as a placebo-controlled, double-blind clinical trial showed a reduction of RBC transfusion as well as a reduction of the need for massive transfusion when rFVIIa at fairly high doses of 100 or 200 mcg/kg was used. The treatment groups and the placebo group had similar numbers of thromboembolic events. The second study (4) was done retrospectively in trauma patients who received 40 mcg/kg of rFVIIa with an option to repeat the dose once if needed. The rFVIIa group required fewer RBC transfusions than the control group. The treatment group also required fewer platelet and cryoprecipitate transfusions. However, there was no difference in mortality.

The above literature gave increasing impetus for clinicians to begin using rFVIIa more liberally in the clinical setting. The US Food and Drug Administration, however, has only licensed the use of rFVIIa for bleeding in patients with hemophilia A or B and inhibitors to factors VIII or IX. In the January 18, 2006 edition of JAMA, an article entitled “Thromboembolic Adverse Events After Use of Recombinant Human Coagulation Factor VIIa” was published (5). This data was gleaned from the FDA’s Adverse Event Reporting System in the time period between March 25, 1999 and December 31, 2004. There were a total of 431 adverse events reported, of which 168 reports described 185 thromboembolic events. 59 events occurred in post licensure trials. Unlabeled indications accounted for 151 of the events, most in patients with active bleeding. There were 50 reported deaths with the probable cause being a thromboembolic event. This article proves to remind the clinician that more research is needed to establish the safety and efficacy of rFVIIa in patients without hemophilia.

In our institution we are currently looking at using rFVIIa for a number of indications including non-fatal CNS bleeding within six hours of bleeding onset, acute bleeding associated with liver disease or warfarin use, uncontrolled hemorrhage in trauma, uncontrolled surgical hemorrhage despite the use of replacement hemostatic factors, and acute bleeding in patients with hemophilia. The dose varies based on the clinical indication. For CNS bleeding, acute bleeding associated with warfarin, and uncontrolled hemorrhage associated with trauma, we are beginning with the dose of 40 mcg/kg. The dose is higher for surgical hemorrhage and bleeding associated with hemophilia.

In conclusion, there is a growing body of literature demonstrating the benefit of the use of rFVIIa. However, it must be used cautiously due to the potential for thromboembolic events and patients should be screened for their risk for these events. More research into the safety, efficacy, and clinical indications is needed. Hospitals should involve pharmacists, clinicians, and hematologists as they develop their protocols for use and dosages.

BIBLIOGRAPHY:
1.) Sorensen B, Johansen P, Nielsen G, et al. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagulation and Fibrinolysis 2003;14(5):469-477.
2.) Mayer S, Brun N, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. The New England Journal of Medicine 2005;352(8):777-785.
3.) Boffard D, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. The Journal of Trauma 2005;59(1):8-16.
4.) Harrison T, Laskoky J, Jazaeri O, et al. Low-dose recombinant activated factor VII results in less blood and blood product use in traumatic hemorrhage. The Journal of Trauma 2005;59(1):150-154.
5.) O’Connell K, Wood J, Wise R, Lozier J, Braun M. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295(3):293-298.