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Frequently Asked Questions

What is the role of recombinant activated Factor VII in intracranial hemorrhage?

Background
Spontaneous intracranial hemorrhage (ICH), accounting for 15% of all strokes in the United States, is the most serious type of hemorrhagic stroke that may occur and has the highest mortality rate among all types of stroke.1 Diagnosis of ICH includes the use of magnetic resonance imaging (MRI) and computed tomography (CT) scans to view images of the brain to determine the site of the hemorrhage and estimate the volume of the hematoma.2 Hematoma volume is known to be the best predictor of mortality in patients with ICH along with level of consciousness and the presence of intraventricular hemorrhage.1 Furthermore, early hematoma growth has been linked to neurologic deterioration. Studies show that patients have a greater increase in hematoma volume within the first 4 to 6 hours of ICH onset. Therefore, treatments that decrease the hematoma volume within this time period are believed to improve clinical outcomes.

According to the 2007 guidelines for the management of spontaneous ICH, treatment modalities are mainly supportive and may involve surgical evacuation of the hematoma.2 The supportive measures include reducing blood pressure (if the systolic blood pressure is greater than 180 mmHg), seizure treatment, glycemic control, and prophylaxis of deep vein thrombosis using intermittent pneumatic compression. In addition, if the ICH is due to impaired coagulation from heparin or warfarin, the guidelines recommend the use of protamine sulfate and vitamin K, respectively, to reverse the anticoagulant effects of these agents. The guidelines state that treatment with recombinant activated factor VII (rFVIIa) has shown promise in a Phase II trial, but further studies are warranted before routine use of the agent can be recommended.

Recombinant activated factor VII is a clotting factor indicated for use in the management of hemophilia, but it also has many off-label uses.3 These off-label indications include the reversal of warfarin-induced major bleeding, intraoperative hemorrhage, disseminated intravascular coagulation, and uremic hemorrhage. In healthy individuals, factor VII (FVII) is part of the extrinsic coagulation pathway, which is activated in response to tissue injury.3-5 Activated FVII and tissue factor then activate Factor X, which converts prothrombin to thrombin, leading to platelet activation. Once thrombin has been produced, it then acts as a factor that converts fibrinogen to fibrin and activates Factor XIII, leading to the formation of a clot. The theory behind using rFVIIa in non-hemophiliac patients with tissue injury is that rFVIIa will enhance the process of clot formation at the site of the blood vessel injury. However, the perceived benefit of using rFVIIa may be negated by the notion that patients with atherosclerotic lesions may be at greater risk of an arterial thromboembolic event (myocardial or cerebral infarction) after the administration of rFVIIa.

Literature Review
In 2005, a phase II study was conducted to evaluate the use of rFVIIa in patients with ICH, which is the basis for the statement on rFVIIa in the current ICH guidelines. In the study, 399 patients were randomized to receive treatment with placebo (n=96) or rFVIIa given within 3 hours after the onset of ICH in doses of 40 (n=108), 80 (n=92), and 160 mcg/kg (n=103).6 The primary outcome was the mean percent change in the volume of ICH 24 hours after baseline CT scan. Clinical outcomes (death and functional ability) and safety were also assessed.

The researchers found that hematoma volume increased significantly in the placebo group compared to the combined rFVIIa groups (29% vs. 14% increase, p=0.01).5 The group receiving 160 mcg/kg was the only group that had a significant difference in hematoma volume from placebo when considered individually (11% vs. 29% increase, p = 0.02). The clinical outcome, mortality at 90 days, was significantly reduced in the 3 treatment groups (combined) compared to placebo (18% vs. 29%, p=0.02), but when each dose was compared to placebo individually there was no significant reduction in 90-day mortality. Active therapy was associated with improved functioning as noted by improvement on the Rankin scale. Overall, the proportion of patients who died or were disabled was 69% in the placebo group vs. 53% in the combined treatment group (difference 16%, 95% confidence interval [CI] 5 to 27, p=0.004). Although the rates of serious thromboembolic events were not significantly different between groups (2% placebo vs. 7% rFVIIa combined, p=0.12), the rate of aterial thromboembolic events was higher in the treatment group (5% vs. 0%, p=0.01). Overall, the researchers concluded that rFVIIa may be a viable option in the treatment of ICH for reducing mortality and improving functional ability, but safety data were inconclusive to make any concrete recommendations regarding its use.

A review evaluated 3 previous phase I and II trials using rFVIIa in ICH and determined the risk of thromboembolic events.5 The inclusion and exclusion criteria were the same in all 3 studies and included rFVIIa doses in a range between 5 to 160 mcg/kg given within 4 hours of ICH symptom onset. There was no difference in venous thromboembolic events between rFVIIa and placebo (8% vs. 5%, p=0.42), but as the dose of rFVIIa increased (120 to 160 mcg/kg) there was a significant increase in arterial thromboembolic events (odds ratio 6.75, 95% CI 1.44 to 31.63, p=0.02). Consequently, receipt of high dose rFVIIa was the only risk factor associated with arterial thromboembolic events in patients with ICH.

The Factor Seven for Acute Hemorrhagic Stroke (FAST) trial, a Phase III, multicenter, randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of using rFVIIa in patients with ICH.7 The study randomized 841 patients with ICH to receive treatment with placebo (n=268) or rFVIIa given in doses of 20 (n=276) or 80 mcg/kg (n=297) within 4 hours of ICH onset. The primary endpoint was poor outcome, which was defined as severe disability (using the modified Rankin scale to evaluate global disability/handicap) or death 90 days after ICH. Secondary endpoints were measured at 90 days and included scores for the Barthel index (to evaluate activities of daily living), Extended Glasgow Outcomes scale, National Institutes of Health Stroke Scale (NIHSS), EuroQol scale, and the Revised Hamilton Rating Scale for Depression.

At study completion, hematoma volumes increased significantly in the placebo group (26% increase) as compared to the 80 mcg/kg rFVIIa group (11%, p<0.001).7 The estimated increase in volume for the 80 mcg/kg group was 3.8 mL vs. 7.5 mL for placebo (p=0.009). No difference was found between placebo and the 20 mcg/kg dose for hematoma volume. The reduction in intracerebral blood volumes did not affect the primary endpoint, poor outcomes at 90 days. There were no significant differences in the number of patients who experienced a poor outcome among the 3 groups (24% placebo vs. 26% 20 mcg/kg group vs. 29% 80 mcg/kg group, p>0.05 for all comparisons). The only secondary outcome that achieved statistical significance was a lower NIHSS score in the 80 mcg/kg rFVIIa group compared to the placebo group (p = 0.02); however, the authors state that this was a small difference in terms of magnitude. There was no difference in the number of thromboembolic events seen among the 3 groups. Although there was no increase in the number of venous thromboembolic events in patients receiving rFVIIa, there was a significant increase in arterial thromboembolic events in patients receiving 80 mcg/kg (p = 0.04 vs. placebo). The researchers also determined that age and previous use of an antiplatelet agent were significant risk factors for the development of thromboembolic events when using rFVIIa. It is worth noting that the researchers did not exclude patients that had any history of a past thromboembolic event, which differs from the phase II study summarized above. The authors concluded that rFVIIa therapy reduced the growth of the hematoma in patients with ICH, but failed to improve survival or functional ability.

Conclusion
The results of the FAST trial do not support the use of rFVIIa in the medical management of ICH. Although the use of rFVIIa may be useful in limiting the growth of ICH-associated hematoma, it does not decrease the incidence of mortality or functional disability and is associated with an increased risk of arterial thromboembolic events.

References

  1. Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke. 2003;34(1):224-229.
  2. Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update. Stroke. 2007;38(6):2001-2023.
  3. Coagulation Factor VIIA. In: DRUGDEX System [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically.
  4. Bickert B, Kwiatkowski JL. Coagulation disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York, NY: McGraw-Hill; 2005:1833-1854.
  5. Diringer MN, Skolnik BE, Mayer SA, et al. Risk of thromboembolic events in controlled trials of rFVIIa in spontaneous intracerebral hemorrhage. Stroke. 2008;39(3):850-856.
  6. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352(8):777-785.
  7. Mayer SA, Brun NC, Betrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358(20):2127-2137.

 

By: Nick Panos, PharmD