Author(s): Joseph P Broderick, MDa; Andrew M Naidech, MD MSPHd; Jordan J Elm, PhDe; Kazunori Toyoda, MDf; Dar Dowlatshahi, MD PhDg; Andrew M Demchuk, MDh; Pooja Khatri, MD MSci; Thorsten Steiner, MDj,k; Philip M Bath, FMedSci DScl; Heinrich J Audebert, MDm; Achala Vagal, MDb; Sohei Yoshimura, MDf; Stephan A Mayer, MDn; Lily L Wang, MBBSb; Noor Sabagha, PharmDa; J D Mocco, MDo; Carlos Molina, MDp; Richard Aviv, MDq; Emily Stinson, MSa; Syed A Quadri, MDa; Janice Carrozzella, MSNb; Thien Huynh, MDr; Anh Phan, MSe; Jonathan Beall, PhDe; Iris Davis, MSa; Nobuyuki Sakai, MDs; Tsuyoshi Ohta, MD PhDs; Michiko Yokosawa, MDt; Takayuki Hara, MDu; Navdeep Sangha, MDv; Kenichi Morita, MD PhDw; Ming Yin Dominc Tse, MBChBx; Christopher D Streib, MDy; Fumio Miyashita, MDz; Yolanda Silva, MDaa; Yoshinari Nagakane, MD PhDab; Tudor Gheorghiu, MDac; Chung-Huan Sun, MDad; Teruyuki Hirano, MDae; Sven Poli, MDaf; Tsuyoshi Izumo, MDag; Mayumi Fukuda-Doi, MDah; Masafumi Ihara, MDai; Masatoshi Koga, MD PhDf; Brian Buck, MDaj; Kyle B Walsh, MDc; Ilana Spokovny, MDak; James C Grotta, MDal
BACKGROUND
Recombinant factor VIIa has been shown to slow bleeding in patients with intracerebral haemorrhage (ICH), but no haemostatic agent has been shown to improve clinical outcomes. We aimed to evaluate the safety, clinical efficacy, and effect on growth of ICH and intraventricular haemorrhage (IVH) of recombinant factor VIIa in patients with acute spontaneous ICH who were most likely to benefit from treatment with this agent.
METHODS
We conducted a multicentre, prospective, double-blind, randomised, placebo-controlled, adaptive, phase 3 trial (FASTEST) at 93 sites across the USA, Japan, Canada, Spain, Germany, and the UK. Adults aged 18–80 years with a spontaneous ICH of 2–60 mL, IVH in less than two-thirds of one lateral ventricle or in less than a third of both lateral ventricles, a Glasgow Coma Scale score of at least 8, no evidence of recent ischaemic stroke or myocardial infarction, no recent use of anticoagulation medication or other structural cause of ICH, and who had been treated with study medication within 2 h of stroke onset or last known well were eligible for inclusion. Patients were randomly assigned (1:1) by a simple randomisation scheme to either 80 μg/kg recombinant factor VIIa (intervention group) or an identical placebo (placebo group), administered intravenously over 2 min. All investigators and participants were masked to allocated group assignment. The primary outcome was functional outcome at 180 days, measured by modified Rankin Scale (mRS; score 0–2, 3, and 4–6) and analysed by intention to treat in all randomly assigned patients. The primary safety outcome was life-threatening thromboembolic events during the first 4 days, assessed in all randomly assigned participants. The secondary aim was change in ICH volume and ICH plus IVH volume between baseline and 24 h of treatment administration. We performed an ordinal logistic regression, adjusted for age, baseline ICH volume, baseline IVH volume, and pre-stroke mRS. Preplanned interim analyses, including adaptive sample size re-estimation and enrichment to a younger subgroup (aged ≤70 years), were also conducted. This trial is registered with ClinicalTrials.gov (NCT03496883) and is closed to new participants.
FINDINGS
Between Dec 3, 2021, and Oct 1, 2025, we screened 3288 patients, of whom 626 participants were randomly assigned and included in the intention-to-treat analyses: 298 (48%) in the placebo group and 328 (52%) in the intervention group. 216 (35%) participants were female and 410 (65%) were male, with a mean age of 61 years (SD 12). Mean time from stroke onset to administration of study drug was 100 min (SD 22). The trial met the prespecified stopping criteria for futility at the second interim analysis. There was no differential effect in the primary clinical outcome measure of mRS at 180 days between the intervention group and placebo group (adjusted common odds ratio 1·09 [95% CI 0·79–1·51]; p=0·61). Life-threatening thromboembolic complications within 4 days occurred in 15 (<5%) participants in the intervention group and in four (1%) in the placebo group (relative risk 3·41 [95% CI 1·14–10·15]; p=0·020). Compared with placebo, recombinant factor VIIa was associated with decreased growth of ICH (–3·7 mL [95% CI –5·4 to –1·9]) and of ICH plus IVH growth (–5·2 mL [–7·6 to –2·8]) between baseline and CT scan at 24 h.
INTERPRETATION
Recombinant factor VIIa administered within 2 h of ICH onset slowed haematoma growth, but did not improve functional outcomes and showed a small increased risk of life-threatening thromboembolic complications. Further testing of recombinant factor VIIa in patients with the greatest risk of continued bleeding is ongoing.
FUNDING
National Institute of Neurological Diseases and Stroke, Japan Agency for Medical Research and Development, and Novo Nordisk.
Author Affiliations
aDepartment of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA; bDepartment of Radiology, University of Cincinnati, Cincinnati, OH, USA; cDepartment of Emergency Medicine, University of Cincinnati, Cincinnati, OH, USA; dDepartment of Neurology, Northwestern Medicine, Chicago, IL, USA; eDepartment of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA; fDepartment of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan; gDivision of Neurology, Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada; hDepartment of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; iDepartment of Neurology, Yale School of Medicine, New Haven, CT, USA; jDepartment of Neurology, Varisano Klinikum Frankfurt Höchst, Frankfurt, Germany; kDepartment of Neurology, Heidelberg University Hospital, Heidelberg, Germany; lStroke Trials Unit, Mental Health & Clinical Neuroscience, Queens Medical Centre, University of Nottingham, Nottingham, UK; mDepartment of Neurology and Center for Stroke Research Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany; nNew York Medical College, Valhalla, NY, USA; oDepartment of Neurosurgery, Icahn School of Medicine, Mount Sinai Health System, New York, NY, USA; pDepartment of Neurology, Stroke Unit, Vall d’Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain; qDepartment of Radiology, Radiation Oncology and Medical Physics, University of Ottawa, Ottawa, ON, Canada; rDepartment of Radiology, Mayo Clinic, Jacksonville, FL, USA; sDepartment of Neurosurgery, Kobe City Medical Center General Hospital, Hyogo, Japan; tDepartment of Neurosurgery, Iwate Prefectural Central Hospital, Morioka, Japan; uDepartment of Neurosurgery, Toranomon Hospital, Tokyo, Japan; vDepartment of Neurology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA; wDepartment of Cerebrovascular Medicine, Niigata City General Hospital, Niigata, Japan; xUniversity of British Columbia, Vancouver, BC, Canada; yDepartment of Neurology, University of Minnesota, Minneapolis, MN, USA; zDivision of Neurology, Kagoshima City Hospital, Kagoshima, Kagoshima, Japan; aaHospital Universitari de Girona, Dr Josep Trueta, IDIBG, Girona, Spain; abDepartment of Neurology, Kyoto Second Red Cross Hospital, Kyoto, Japan; acDepartment of Neurology, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; adNeuroscience Institute, The Queen’s Medical Center, Honolulu, Hawaii; aeDepartment of Stroke and Cerebrovascular Medicine, Kyorin University School of Medicine, Tokyo, Japan; afDepartment of Neurology and Stroke and Hertie-Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany; agDepartment of Neurosurgery, Gifu University Graduate School of Medicine, Nagasaki, Japan; ahDepartment of Data Science, National Cerebral and Cardiovascular Center, Osaka, Japan; aiDepartment of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan; ajUniversity of Alberta, Edmonton, AB, Canada; akDepartment of Neurology, Sutter Health, Mills Peninsula Medical Center, Burlingame, CA USA; alMemorial Hermann Hospital-Texas Medical Center, Houston, TX, USA
