title: Risk of thromboembolic events in controlled trials of rFVIIa in spontaneous intracerebral hemorrhage.
abstract: OBJECTIVE
  Recombinant activated factor VII (rFVIIa) reduces hematoma expansion and improves outcome after intracerebral hemorrhage (ICH), with an apparent increase in nonfatal thromboembolic events (TEs) with higher doses. Despite low incidences of such events in rFVIIa-treated hemophiliacs, the frequency in older patients with more atherosclerosis and immobility has yet to be defined.
  
  
  METHODS
  Data were pooled from 3 randomized placebo-controlled studies in patients diagnosed within 3 hours of spontaneous ICH who received a single dose of rFVIIa (5 to 160 microg/kg; n=371) or placebo (n=115). Clinical/laboratory evaluations, lower extremity Doppler studies, and 72-hour CT scans were used to monitor for TEs. Adverse events occurring while hospitalized and serious events occurring through day 90 were carefully reviewed.
  
  
  RESULTS
  There was no overall increase in risk of total TEs in rFVIIa-treated patents; however, there were more arterial, but not venous, TEs in the high dose group (120 to 160 microg/kg) compared with placebo (5.4% versus 1.7%; P=0.13). Arterial events occurring within 7 days of drug administration classified as possibly or probably associated with study drug included myocardial ischemia (n=9, 8 were non-ST-segment elevation and non-Q-wave events; 2 of the 9 had sequelae) and ischemic stroke (n=9, 4 of which had likely causes other than rFVIIa). Regression analysis identified high doses (120 to 160 microg/kg) of rFVIIa as the only factor associated with arterial TEs (odds ratio=6.75; P=0.02).
  
  
  CONCLUSIONS
  There appears to be a increased risk of arterial TEs associated with higher doses of rFVIIa in ICH patients as compared with placebo. Further studies are underway to identify specific factors associated with these events and to define the dose that maximizes benefit and minimizes risk.
authors.affiliation: Department of Neurology, Campus Box 8111, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO 63110, USA. diringerm@neuro.wustl.edu
authors.forename: Michael N
authors.initials: MN
authors.lastname: Diringer
authors.forename: Brett E
authors.initials: BE
authors.lastname: Skolnick
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Mayer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Steiner
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Davis
authors.forename: Nikolai C
authors.initials: NC
authors.lastname: Brun
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Broderick
mesh_terms: D000368:Aged; D002545:Brain Ischemia / Q000139:chemically induced / Q000150:complications; D002543:Cerebral Hemorrhage / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D015942:Factor VIIa / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000139:chemically induced / Q000150:complications; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012044:Regression Analysis; D018570:Risk Assessment; D020521:Stroke / Q000453:epidemiology / Q000209:etiology; D013923:Thromboembolism / Q000139:chemically induced* / Q000453:epidemiology
chemical_list: D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa