Source: Logan AC, Yank V, Stafford RS. Off-label use of recombinant factor VIIa in U.S. Hospitals: analysis of hospital records. Ann Intern Med. 154(8): 516-522, April 2011.

Al-Shahi Salman R. Haemostatic drug therapies for acute spontaneous intracerebral hemorrhage. Cochrane Database of System Rev 2009, Issue 4. Art No.: CD005951.

Diringer MN, Skolnick BE, Mayer SA, et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the factor seven for acute hemorrhagic stroke (FAST) trial. Stroke. 41(1): 48-53, 2010 Jan.

Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 358(20): 2127-2137, 2008 May.

Yuan ZH, Jiang JK, Huang WD, et al. A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. Journal of Clinical Neuroscience. 17(6):685-93, 2010 Jun.

Narayan K, Maas AI, Marshall LF, et al. Recombinant factor VIIA in traumatic intracerebral hemorrhage: results of a dose-escalation clinical trial. Neurosurgery. 62(4): 776–786, 2008 April.

Levi M, Levy JH, Andersen HF, and Truloff D. Safety of Recombinant Activated Factor VII in Randomized Clinical Trials. N Engl E Med 363;19: 1791-1800, 2010 Nov.

Efficacy Endpoints: Mortality and Dependence

Harm Endpoints: Thromboembolic Events

Narrative: Spontaneous intracerebral hemorrhage (ICH) accounts for 10% of strokes. Approximately 40% die in the first month and 62% die in the first year. Larger hematomas are associated with increased mortality so a drug that limits the early expansion of ICH could theoretically improve mortality and functional outcome. Recombinant activated factor VII (rFVIIa) is believed to bind to exposed tissue factor and activated platelets, eventually generating thrombin. It is FDA approved for the treatment of bleeding in hemophilia A and B, but 97% of uses are currently off-label: 11% of these are for ICH, 29% for cardiovascular surgery, and 29% for trauma.1

The Cochrane Review analyzed all published and unpublished randomized controlled trials evaluating hemostatic drugs in ICH.2 A total of 1398 patients within 4 hours ICH onset were included: 975 subjects received rFVIIa, 2 epsilon-aminocaproic acid (EACA), and 423 placebo. The primary endpoints were mortality and dependence at 90 days. There was no significant difference in the risk of death (18.5% vs 19.4% for placebo, RR 0.85) and no difference in the combination of ‘death or dependence’ (49.6% vs 51.7%, RR 0.91). There was also no significant difference in thromboembolic events (8.5% vs 6.2%, RR 1.37). However updated publications from one of the trials suggest that there was a statistically significant increase in arterial events among subjects in the high dose rFVIIa group.3,4 Similar conclusions were made in a recent meta-analysis regarding the increased risk of arterial events with rFVIIa in both spontaneous and traumatic ICH.5,6 In addition, a recent systematic review of trials involving rFVIIa suggests that there is a roughly 2% (1 in 50) increase in arterial thrombotic complications with the drug. However, these adverse effects increased by more than 5% (1 in 20) among subjects >65 years of age, and nearly 7% (1 in 15) among those >75.7 ICH occurs predominantly in the elderly and this adverse effect profile may help to explain the lack of benefit shown in trials assessing clinical outcomes.

Adding the new 2010 data from the FAST trial to the Cochrane review, the risk for thromboembolic events for rFVIIa is 181 of 921 patients (19.7%) and for placebo is 70 of 409 patients (17.1%), but this is not a significant difference.2,3

Caveats: In the trials assessing rFVIIa adverse event reporting was suboptimal, clinical outcome assessments were often unblinded, and follow-up was generally incomplete. In addition, exclusion criteria for the FAST trial were changed mid-study and the Cochrane review authors have reported difficulty obtaining further information from the industry sponsor that controls the data (Novo Nordisk).2,6 These issues highlight the fact that available published data may be a fraction of the complete data on this drug, and that the available data are likely to represent an optimistic view of the drug’s performance.

Despite this these data do not support the use of rFVIIa for the treatment of spontaneous ICH. While off label use of rFVIIa continues to climb despite the absence of trial evidence to support this practice, use for ICH has decreased since the publication of the FAST trial.

Author: Dan Rolston, MD, MS

Published/Updated: June 4, 2011